Piperidine compounds, pharmaceutical composition comprising the same and its use

ABSTRACT

Piperidine compounds and pharmaceutically useful salts thereof, a pharmaceutical composition including an effective amount of the racemic or enantiomerically enriched piperidine compounds to treat gastrointestinal diseases, and a method of treating gastrointestinal diseases in a mammal are provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/248,872 filed Aug. 26, 2016 which is a divisional of U.S. applicationSer. No. 14/158,517, now U.S. Pat. No. 9,593,102, filed Jan. 17, 2014which is a divisional application of U.S. application Ser. No.12/576,494, now U.S. Pat. No. 8,642,772, filed Oct. 9, 2009, whichclaims the benefit and priority to U.S. Provisional Application No.61/105,070 filed Oct. 14, 2008. The entire disclosures of theapplications identified in this paragraph are incorporated herein byreferences.

TECHNICAL FIELD

The present invention relates, in general, to a piperidine compound andpharmaceutically useful salts thereof, a pharmaceutical compositionincluding an effective amount of racemic or enantiomerically enrichedpiperidine compounds to treat gastrointestinal diseases, and a method oftreating gastrointestinal diseases in a mammal. More particularly, thepresent invention relates to racemic or enantiomerically enrichedO-carbamoyl and hydroxyl piperidine compounds and pharmaceuticallyuseful salts thereof, that are useful to treat irritable bowel syndrome(IBS), gastric motility disorder, and visceral pain.

BACKGROUND

Many reports have disclosed that piperidine compounds are effectivelyused for controlling various gastrointestinal diseases, especially forirritable bowel syndrome and gastric motility disorders.

For example,cis-4-amino-5-chloro-N—[1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide(general name: Cisapride) has been widely used in the clinical field asa gastrointestinal motility enhancer or as a gastrointestinal prokineticagent, and other piperidine compounds have been disclosed in manypatents (WO2005/092882, WO1999/055674, WO2005/021539, WO04/026868,WO04/094418, WO99/02494) as therapeutic medicines for managinggastrointestinal diseases.

Active research and development efforts have continued to be directed tothe application of piperidine compounds for the treatment ofgastrointestinal diseases.

SUMMARY

Certain embodiments provide a piperidine compound and/or apharmaceutically-acceptable salt thereof, a pharmaceutical compositionincluding an effective amount of a piperidine compound and/or apharmaceutically-acceptable salt thereof for treating a gastrointestinaldisease, and a method of treating diseases in a mammal, such asirritable bowel syndrome (IBS), gastric motility disorder, and/orvisceral pain.

Certain embodiments provide a method of treating disorders in a mammalby administering an effective amount of racemic or enantiomericallyenriched piperidine compound represented by the below structural formula(I), in particular, the compounds represented by the below structuralformulae (IV) and (V), and a pharmaceutically acceptable carrier to amammal in need of irritable bowel syndrome (IBS) or gastric motilitydisorder therapy.

DESCRIPTION

A more complete appreciation of the invention, and many of the attendantadvantages thereof, will be readily apparent as the same becomes betterunderstood by reference to the following detailed description.

In an embodiment, a piperidine compound, represented by the followingstructural formula (I), and pharmaceutically acceptable salts thereofare provided,

-   -   wherein:    -   m is an integer of 1 or 2;    -   n is an integer of 0 to 2, preferably 0;

A is selected from the group consisting of a phenyl group and abenzimidazole group, wherein the phenyl group may be substituted withone or more identical or different groups independently selected fromthe group consisting of hydrogen, a C1-C6 linear or branched alkylgroup, a C1-C6 linear or branched alkoxy group, an amino group, and ahalogen, and the benzimidazole group may be substituted with one or moreidentical or different groups independently selected from the groupconsisting of hydrogen, a C1-C6 linear or branched alkyl group, a C1-C6linear or branched alkoxy group, a C3-C7 cyclic alkyl group, an aminogroup, a halogen, and an oxo group;

X is a hydroxy or OCONR₁R₂ wherein R₁ and R₂ may be the same ordifferent and independently selected from the group consisting ofhydrogen, a C1-C6 linear or branched alkyl group, a benzyl group, and a5- to 7-membered cyclic or heterocyclic compound that may be substitutedwith one or more identical or different groups independently selectedfrom the group consisting of a C1 to C6 alkyl, or R₁ and R₂ may form a5- to 7-membered heterocyclic ring together with a nitrogen atom towhich they are attached; and

B is selected from the group consisting of a phenyl group, a phenoxygroup, a thienyl group, and a naphthyl group, wherein the phenyl group,phenoxy group, thienyl group, or naphthyl group may be substituted withone or more identical or different groups independently selected fromthe group consisting of hydrogen, halogen, nitro, cyano,methanesulfonyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy,phenyl, a C11-C6 linear or branched alkyl group, and a C1-C6 linear orbranched alkoxy group.

In the definition of the substituents, the alkyl group may be selectedfrom the group consisting of a methyl, an ethyl, a linear or branchedpropyl, a linear or branched butyl, a cyclopropyl, a cyclobutyl, acyclopentyl, a cyclohexyl, and a benzyl. The halogen is selected fromfluoro, chloro, bromo, and iodo atoms.

In an embodiment, substituent A in structural formula (I) may be aphenyl group that may be substituted with one or more identical ordifferent groups independently selected from the group consisting ofhydrogen, a halogen, an amino group, a C1-C6 linear or branched alkylgroup, or a C1-C6 linear and branched alkoxy group.

Substituent A may be represented by structural formula (II):

-   -   wherein R3 is a substituted or unsubstituted C1 to C6 linear or        branched alkyl.

When substituent A in structural formula (I) has structural formula(II), the piperidine compound is represented by the following structuralformula (IV):

-   -   wherein m, n, X, B, and R3 are defined as above.

The examples of the compound having the chemical formula (IV) mayinclude of4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidin-4-yl]methyl]-2-methoxybenzamide;

-   4-amino-5-chloro-N-[[1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamide:hydrochloride;-   4-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-methylphenyl)ethyl]piperidin-4-yl]methyl]-2-methoxybenzamide:hydrochloride;-   4-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-methoxyphenyl)ethyl]piperidin-4-yl]methyl]-2-methoxybenzamide:hydrochloride;-   4-amino-5-chloro-N-[[1-[2-(4-chlorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamide:hydrochloride;-   4-amino-5-chloro-N-[[1-[2-(3,4-dichlorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamide:hydrochloride;-   4-amino-5-chloro-N-[[1-[2-hydroxy-2-[4-(trifluoromethyl)phenyl]ethyl]piperidin-4-yl]methyl]-2-methoxybenzamide:hydrochloride;-   4-amino-5-chloro-N-[[1-[2-(3,4-difluorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamide:hydrochloride;-   [2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-phenylethyl]carbamate:hydrochloride;-   [2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-fluorophenyl)ethyl]carbamate:hydrochloride;-   [2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(3,4-dichlorophenyl)ethyl]carbamate:hydrochloride;-   [2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(3,4-difluorophenyl)ethyl]carbamate:hydrochloride;-   [2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-[4-(trifluoromethyl)phenyl]ethyl]carbamate:hydrochloride;-   4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide:hydrochloride;-   4-amino-5-chloro-N-[[1-[3-(4-fluorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide:hydrochloride;-   4-amino-5-chloro-N-[[1-[3-(3,4-dichlorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide:hydrochloride;-   4-amino-5-chloro-N-[[1-(3-hydroxy-3-thiophen-2-ylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide:hydrochloride;-   4-amino-5-chloro-N-[[1-[4-(4-fluorophenyl)-3-hydroxybutyl]piperidin-4-yl]methyl]-2-methoxybenzamide:hydrochloride;-   4-amino-5-chloro-N—[[1-[5-(4-fluorophenyl)-3-hydroxypentyl]piperidin-4-yl]methyl]-2-methoxybenzamide:hydrochloride;-   [3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-chlorophenyl)propyl]carbamate:hydrochloride;-   [4-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-fluorophenyl)butan-2-yl]carbamate:hydrochloride;-   [1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-5-(4-fluorophenyl)pentan-3-yl]carbamate:hydrochloride;-   4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-methoxybenzamide:hydrochloride;-   4-amino-5-chloro-N-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide:hydrochloride;-   4-amino-5-chloro-N-[[1-[2-hydroxy-3-[4-(trifluoromethyl)phenoxy]propyl]piperidin-4-yl]methyl]-2-methoxybenzamide:hydrochloride;-   [1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-phenoxypropan-2-yl]carbamate:hydrochloride;-   [1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-(4-fluorophenoxy)propan-2-yl]3,5-dimethylpiperidine-1-carboxylate:hydrochloride-   [1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-(4-methoxyphenoxy)propan-2-yl]carbamate:hydrochloride;-   [1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-(2,3-dichlorophenoxy)propan-2-yl]azepane-1-carboxylate:hydrochloride;-   4-amino-5-chloro-N-[[1-[(2S)-2-hydroxy-2-phenylethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;-   4-amino-5-chloro-N-[[1-[(2R)-2-hydroxy-2-phenylethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;-   4-amino-5-chloro-N-[[1-[3-(4-chlorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;-   [3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-fluorophenyl)propyl]carbamate;-   (R)-[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-fluorophenyl)propyl]carbamate;-   (S)-[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-fluorophenyl)propyl]carbamate;-   4-amino-5-chloro-N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidin-4-yl]methyl]-2-methoxybenzamide;-   [1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-phenoxypropan-2-yl]piperidine-1-carboxylate;    and-   4-amino-5-chloro-N-[[1-[3-(2,5-dichlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide.

In another embodiment, substituent A may be a benzimidazole group thatmay be substituted with one or more identical or different groupsindependently selected from the group consisting of hydrogen, a C1-C6linear or branched alkyl group, a C1-C6 linear or branched alkoxy group,a C3-C7 cyclic alkyl group, an amino group, a halogen, and an oxo group.

Substituent A in structural formula (I) is represented by structuralformula (III):

-   -   wherein R4 is C1-C6 linear or branched alkyl group, or a C3-C7        cyclic alkyl that may be substituted or unsubstituted.

When substituent A in structural formula (I) has structural formula(III), the piperidine compound is represented by the followingstructural formula (V):

The examples of the compound having the chemical formula (V) may include[1-(2-methylphenoxy)-3-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]propan-2-yl]carbamate;

-   N-[[1-[2-hydroxy-3-(4-nitrophenoxy)propyl]piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide:hydrochloride;-   N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide:hydrochloride;-   N-[[1-[3-(4-fluorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-3-methyl-2-oxobenzimidazole-1-carboxamide:hydrochloride;-   3-ethyl-N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide:hydrochloride;-   [1-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]-3-phenoxypropan-2-yl]carbamate:hydrochlorid;-   [1-(4-fluorophenoxy)-3-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]propan-2-yl]carbamate:hydrochloride;-   [1-(4-methoxyphenoxy)-3-[4-[[(3-methyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]propan-2-yl]carbamate:hydrochloride;-   [1-[4-[[(3-ethyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]-3-phenoxypropan-2-yl]carbamate:hydrochloride;-   [1-(4-chlorophenoxy)-3-[4-[[(3-ethyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]propan-2-yl]carbamate:hydrochloride;-   3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide:hydrochloride;-   3-cyclopropyl-N-[[1-[3-(4-fluorophenyl)-3-hydroxypropyl]piperidin-1-ium-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide:hydrochloride;-   [3-[4-[[(3-cyclopropyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]-1-phenylpropyl]carbamate:hydrochloride;-   [1-(4-fluorophenyl)-3-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]propyl]carbamate:hydrochloride;-   [1-(4-methoxyphenyl)-3-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]propyl]carbamate:hydrochloride;-   N-[[1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide:hydrochloride;-   [1-(4-fluorophenyl)-2-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]ethyl]carbamate:hydrochloride;-   [[2-[4-[[(3-cyclopropyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]-1-(3-methoxyphenyl)ethyl]carbamate:hydrochloride;-   [1-[4-[[(3-methyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]-3-phenoxypropan-2-yl]carbamate;-   N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide;    and-   [3-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]-1-phenylpropyl]carbamate.

In accordance with an embodiment of the present invention, the compoundrepresented by the structural formula (I) and pharmaceutical acceptablesalts thereof can be prepared by the following steps, starting fromamino alcohol compounds represented by the following general structuralformula (VI):

-   -   wherein A, B, m, and n are as described above.

The method for preparing the O-carbamoyl compounds represented by thefollowing general structural formula (VII) will be described below indetail:

-   -   wherein A, B, R1, R2, m, and n are described as above.

The O-carbamoyl compounds represented by the general structural formula(VII) are prepared by reacting an amino alcohol represented by thegeneral structural formula (VI) with 1,1′-carbonyldiimidazole (CDI) andthen with an amine base represented by the following general structuralformula (VIII):NH R1R2  (VIII)

where R1 and R2 are described as above.

This procedure is summarized as set forth in Reaction Scheme 1 below.

The reaction conditions described in Reaction Scheme I are described indetail as follows. For the conversion of the compound (VI) to thecompound (VII), the concentration of the starting material (VI) is about0.005 to 0.1 moles with 1,1′-carbonyldiimidazole (CDI) ranging fromabout 2.0 to 3.0 equivalents. This reaction is preferably carried out ata temperature of 10 to 30° C. Without purification, the resultingintermediate is treated with 1 to 1000 equivalents of an amine baserepresented by the general structural formula (VIII) at a temperature of10 to 30° C. to give the compound of the general structural formula(VII). For this carbamoylation, ethereal solvents such as diethyl etherand tetrahydrofuran, a halogenated hydrocarbon solvent such asdichloromethane and chloroform, or a mixture thereof may be used.

In Reaction Scheme I, HX represents an acid that is capable of forming apharmaceutically useful salt with the basic nitrogen atom. Specificexamples of the acid used for the preparation of the compound (IX) fromthe compound (VII) include hydrochloric acid, sulfuric acid, phosphoricacid, acetic acid, benzoic acid, citric acid, malonic acid, salicylicacid, malic acid, fumaric acid, oxalic acid, succinic acid, tartaricacid, lactic acid, gluconic acid, ascorbic acid, maleic acid, asparticacid, benzene sulfonic acid, methane sulfonic acid, ethane sulfonicacid, hydroxymethane sulfonic acid, hydroxyethane sulfonic acid, and thelike. Additional acids can be found by referring to “PharmaceuticalSalts”, J. Pharm. Sci., 1977; 66(1): 1-19. This preparation is executedin a reaction media that can be exemplified by an ethereal solvent suchas tetrahydrofuran, an alcoholic solvent such as methanol, an estersolvent such as ethyl acetate, a halogenated hydrocarbon solvent, andmixtures thereof. An ethereal solvent is recommended as an additionsolution, including ethyl ether, propyl ether, isopropyl ether, butylether, and isobutyl ether. The concentration of the compound (VII) is inthe order of about 0.01 to 5 moles.

The piperidine compounds of structural formula (I) may have all thepossible isomeric forms, such as the racemic, enantiomeric, anddiastereoisomeric forms, and the pharmaceutically acceptable additionsalts with inorganic and/or organic acids or with inorganic and/ororganic bases of said compound of structural formula (I), for thepreparation of medicines intended for the prevention or treatment ofdiseases of the gastrointestinal tract such as irritable bowel syndrome(IBS), gastric motility disorder and/or visceral pain.

The method for preparing the amino alcohol benzamide compoundsrepresented by following structural formula (X) will be described belowin detail:

-   -   wherein B, m, and n are as described above.

The amino alcohol benzamide compounds represented by the generalstructural formula (X) are prepared by reacting piperidine benzamiderepresented by the general structural formula (XI) with an alkyl haliderepresented by the following general structural formula (XII), anepoxide represented by the following general structural formula (XIII),or a Weinreb amide represented by the following general structuralformula (XIV):

-   -   wherein m is an integer of 1 or 2, Z is a halogen, and B is the        same as defined above;

-   -   wherein n is an integer of 0 to 2, preferably 0, and B is the        same as defined above; and

-   -   wherein n is an integer of 0 to 2, preferably 0, and B is the        same as defined above.

This procedure is summarized as set forth in Reaction Scheme II below.

Step II-1

In this step, the desired piperidine compound of structural formula (XV)is prepared by the alkylation of a compound of structural formula (XI)with an alkyl halide (XII) and reduction of the resulting ketone.Details of the reaction conditions described in Step II-1 are asfollows. For the conversion of the compounds (XI) to the compounds (XV),the concentration of the starting material (XI) is about 0.005 to 0.1moles with compound (XII-1) ranging from about 1.1 to 3.0 equivalentsand a base such as potassium carbonate, cesium carbonate, andtriethylamine ranging from about 1.5 to 5.0 equivalents. This reactionis preferably carried out at a temperature of 20 to 80° C. Withoutpurification, the resulting intermediate ketone is treated with 1.0 to10.0 equivalents of NaBH₄ at a temperature of 0 to 30° C. to give thecompound of the general structural formula (XV).

For an alternative conversion of compound (XI) to the compound (XV) inwhich alkyl halide is represented by structural formula (XII-2), theconcentration of the starting material (XI) is about 0.005 to 0.1 moleswith compound (XII-2) ranging from about 1.1 to 3.0 equivalents and abase such as potassium carbonate, cesium carbonates and triethylamineranging from about 1.5 to 5.0 equivalents. This reaction is preferablycarried out at a temperature of 20 to 80° C. For this reaction, anethereal solvent such as diethyl ether and tetrahydrofuran, ahalogenated hydrocarbon solvent such as dichloromethane and chloroform,an alcohol solvent such as methanol, ethanol, and isopropanol, oracetonitrile may be used.

Step II-2

In this step, the piperidine compound (XVI) is prepared by the epoxidering opening reaction.

Details of the reaction conditions described in Step II-2 are asfollows.

For the conversion of the compound (XI) to the compound (XVI), theconcentration of the starting material (XI) is about 0.005 to 0.1 moleswith compound (XIII) ranging from about 1.1 to 3.0 equivalents. Thisreaction is preferably carried out at a temperature of 20 to 80° C. Forthis reaction, ethereal solvents such as diethyl ether andtetrahydrofuran, a halogenated hydrocarbon solvent such asdichloromethane and chloroform, an alcohol solvent such as methanol,ethanol, and isopropanol, or acetonitrile may be used.

Step II-3

In this step, the piperidine compound (XVIII) is prepared by a couplingreaction of a compound of structural formula (XI) with a Weinreb amidecompound of structural formula (XIV), and reduction of a resultingketone compound of structural formula (XVII). Details of the reactionconditions described in Step II-3 are as follows. For the conversion ofthe compounds (XI) to the compounds (XVIII), the concentration of theWeinreb amide (XIV) is about 0.005 to 0.1 moles with vinyl magnesiumbromide ranging from about 1.1 to 2.0 equivalents. Next, the resultingintermediate is treated with a piperidine compound represented by thegeneral compound (XI) and excess water at a temperature 0 to 30° C. togive the compound of the general structural formula (XVII). Withoutpurification, the resulting intermediate ketone is treated with 1.0 to10.0 equivalents of NaBH₄ at a temperature of 0 to 30° C. to give thecompound of the general structural formula (XVIII). For this reaction,an ethereal solvent such as diethyl ether and tetrahydrofuran, ahalogenated hydrocarbon solvent such as dichloromethane and chloroform,an alcohol solvent such as methanol, ethanol, and isopropanol, oracetonitrile may be used.

The method for preparing the amino alcohol benzimidazole compoundsrepresented by the following general structural formula (XIX) will bedescribed below in detail.

-   -   Herein, B, R4, m, and n are as defined above.

The amino alcohol benzimidazole compounds represented by the generalstructural formula (XIX) are prepared by reacting piperidinebenzimidazole represented by the general structural formula (XX) with analkyl halide represented by the following general structural formula(XII) or an epoxide represented by the following general structuralformula (XIII):

-   -   wherein m is an integer of 1 or 2, Z is a halogen, and B is the        same as defined above; and

-   -   wherein n is an integer of 0 to 2, and B is the same as defined        above.

This procedure is summarized as set forth in Reaction Scheme III below.

Step III-1

In this step, the piperidine compound of structural formula (XXI) isprepared by the alkylation of a compound of structural formula (XX) withan alkyl halide and reduction. The reaction may be carried out under thesame conditions as described in Step II-1.

Step III-2

In this step, the piperidine compound of structural formula (XXII) isprepared by the epoxide ring opening reaction. The reaction may becarried out under the same conditions as described in Step II-2.

It should be noted that the stereochemistry of the product (I, IV, or V)depends solely on that of the starting material (XII or XIII); astarting material (XII or XIII) with an (S)-enantiomer yields only aproduct with an (S)-enantiomer, and a starting material (XII or XIII)with an (R)-enantiomer yields only a product with an (R)-enantiomer.

Based on the therapeutic activities of the novel piperidine compounds asshown in the following examples, another embodiment provides apharmaceutical composition including the piperidine compoundsrepresented by structural formula (I), in particular, the compoundsrepresented by structural formula (IV) and (V), as an active ingredient.

In another embodiment, provided is a pharmaceutical compositionincluding an effective amount of the piperidine compounds represented bystructural formula (I), in particular, the compounds represented bystructural formula (IV) and (V), for treating disorders ofgastrointestinal tract such as irritable bowel syndrome,gastrointestinal motility disorder (e.g., gastric motility disorder),constipation, visceral pain, and the like.

Another embodiment provides a method of treating disorders ofgastrointestinal tract, such as irritable bowel syndrome (IBS),gastrointestinal motility disorder (e.g., gastric motility disorder),constipation, and visceral pain, in a mammal including administering thecomposition of the compound of structural formula (I) to a mammal inneed of gastrointestinal tract disorder therapy.

The compounds of structural formula (I) are useful in treating IBS,specifically constipation-predominant IBS, constipation, and othergastrointestinal disorders associated with gastrointestinal motilitydisorder, because they can increase gastrointestinal motility.

Additionally, the compounds of structural formula (I) are useful inalleviating visceral pain caused by IBS and/or other gastrointestinaldisorders, because they can reduce visceral pain and discomfortassociated with IBS and the like.

The compounds of structural formula (I) may be administered orally orparenterally, and alone or in combination with conventionalpharmaceutical carriers. Applicable solid carriers can include one ormore substances that may also act as flavoring agents, lubricants,solubilizers, suspending agents, fillers, glidants, compression aids,binders, tablet-disintegrating agents, or encapsulating materials. Inpowders, the carrier may be a finely divided solid that is in admixturewith the finely divided active ingredient. In tablets, the activeingredient is mixed with a carrier having necessary compressionproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets may contain up to 99% of the activeingredient.

Suitable solid carriers include, for example, calcium phosphate,magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes, and ion exchange resins. Liquidcarriers may be used in preparing solutions, suspensions, emulsions,syrups, and elixirs.

The active ingredient can be dissolved or suspended in apharmaceutically acceptable liquid carrier such as water, an organicsolvent, a mixture of both, or pharmaceutically acceptable oils or fats.The liquid carrier can contain other suitable pharmaceutical additivessuch as solubilizers, emulsifiers, buffers, preservatives, sweeteners,flavoring agents, suspending agents, thickening agents, colors,viscosity regulators, stabilizers, or osmo-regulators. Suitable examplesof liquid carriers for oral and parenteral administration include water(particularly containing additives as above, e.g., cellulosederivatives, preferably a sodium carboxymethyl cellulose solution),alcohols (including monohydric alcohols and polyhydric alcohols, e.g.,glycols) and their derivatives, and oils (e.g., fractionated coconut oiland arachis oil).

For parenteral administration, the carrier can also be an oily estersuch as ethyl oleate and isopropyl myristate. Sterile liquid carriersare used in sterile liquid form compositions for parenteraladministration. Liquid pharmaceutical compositions that are sterilesolutions or suspensions can be utilized by, for example, intramuscular,intraperitoneal, or subcutaneous injection. Sterile solutions can alsobe administered intravenously.

Oral administration may be either in liquid or solid composition form.Preferably, the pharmaceutical compositions containing the presentcompounds are in unit dosage form, e.g., as tablets or capsules. In suchform, the composition is sub-divided in unit dosages containingappropriate quantities of the active ingredients. The unit dosage formscan be packaged compositions, for example, packaged powders, vials,ampoules, prefilled syringes, or sachets containing liquids.Alternatively, the unit dosage form can be, for example, a capsule ortablet itself, or it can be an appropriate number of any suchcompositions in package form. The therapeutically effective dosage to beused may be varied or adjusted by the administering physician, andgenerally ranges from 0.5 mg to 750 mg, according to the specificcondition(s) being treated and the size, age, and response pattern ofthe patient.

The compounds of structural formula (I) may be administered to patientsat a dosage of from 0.7 to 7000 mg per day. For a normal human adultwith a body weight of approximately 70 kg, the administration amount istranslated into a daily dose of 0.01 to 100 mg per kg of body weight.The specific dosage employed, however, may vary depending upon therequirements of the patient, the severity of the patient's condition,and the activity of the compound. The determination of optimum dosagesfor a particular situation must be clinically done, and is within theskill of the

A better understanding of the present art. invention may be obtained inlight of the following examples that are set forth to illustrate, butare not to be construed to limit, the present invention.

EXAMPLE 14-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidin-4-yl]methyl]-2-methoxybenzamide;Hydrochloride

A mixture of4-amino-5-chloro-2-methoxy-N-((piperidin-4-yl)methyl)benzamide (5.0mmol), 2-bromoacetophenone (6.0 mmol), and potassium carbonate (7.6mmol) was stirred in 15 mL of acetonitrile for 2 h. This solution wasthen concentrated in a rotary evaporator and diluted with ethyl acetate.This mixture was then washed with brine, and the resulting organic layerwas dried and purified by column chromatography. This was dissolved inethanol (10 mL) and was added with sodium borohydride (10.0 mmol) at 0°C. and stirred at 25° C. for 2 h. This solution was concentrated on arotary evaporator and diluted with ethylacetate. This mixture was washedwith brine, dried, and concentrated in vacuo. The residue was purifiedby column chromatography. The resulting4-amino-5-chloro-N-((1-(2-hydroxy-2-phenylethyl)piperidin-4-yl)methyl)-2-methoxybenzamidewas dissolved in methylene chloride (MC) and the solution was treatedwith a solution of HCl in ether. The resulting precipitate was filteredto give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.4-7.2 (m, 5H),6.35 (s, 1H), 4.95 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4-3.3 (m, 3H),3.0 (m, 1H), 2.6 (m, 2H), 2.4 (m, 1H), 2.2 (m, 1H), 1.9-1.6 (m, 3H),1.6-1.4 (m, 2H)

EXAMPLE 24-amino-5-chloro-N-[[1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 1 was followed using2-bromo-4′-fluoroacetophenone as a reactant, instead of2-bromoacetophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.15 (m, 2H),7.1-6.95 (m, 2H), 6.35 (s, 1H), 4.9 (m, 1H), 4.4 (s, 2H), 3.9 (m, 3H),3.4-3.2 (m, 3H), 3.1-2.9 (m, 1H), 2.6-2.3 (m, 3H), 2.3-2.1 (m, 1H),1.9-1.7 (m, 3H), 1.6-1.4 (m, 2H)

EXAMPLE 34-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-methylphenyl)ethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 1 was followed using2-bromo-4′-methylacetophenone as a reactant, instead of2-bromoacetophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.3-7.1 (m, 4H), 6.35(s, 1H), 4.9 (m, 1H), 4.4 (s, 2H), 3.9 (m, 3H), 3.5-3.3 (m, 3H), 3.3-3.1(m, 1H), 2.7 (m, 2H), 2.6-2.5 (m, 1H), 2.4 (m, 4H), 1.9-1.7 (m, 3H),1.6-1.5 (m, 2H)

EXAMPLE 44-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-methoxyphenyl)ethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 1 was followed using2-bromo-4′-methoxyacetophenone as a reactant, instead of2-bromoacetophenone, to give the title compound.

1H NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.2 (m, 2H),6.95-6.85 (m, 2H), 6.35 (s, 1H), 4.9 (m, 1H), 4.4 (s, 2H), 3.9 (m, 3H),3.8 (s, 3H), 3.4-3.2 (m, 3H), 3.1-3.0 (m, 1H), 2.6 (m, 2H), 2.5 (m, 1H),2.3-2.1 (m, 1H), 1.9-1.7 (m, 3H), 1.6-1.4 (m, 2H)

EXAMPLE 54-amino-5-chloro-N-[[1-[2-(4-cyanophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 1 was followed using2-bromo-4′-cyanoacetophenone as a reactant, instead of2-bromoacetophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.65 (m, 2H), 7.55(m, 2H), 6.35 (s, 1H), 4.9 (m, 1H), 4.45 (s, 2H), 3.9 (m, 3H), 3.4 (m,2H), 3.2 (m, 1H), 2.95 (m, 1H), 2.7-2.33 (m, 3H), 2.2 (m, 1H), 1.9-1.7(m, 3H), 1.6-1.4 (m, 2H)

EXAMPLE 64-amino-5-chloro-N-[[1-[2-(4-chlorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 1 was followed using2-bromo-4′-chloroacetophenone as a reactant, instead of2-bromoacetophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (m, 1H), 7.8 (m, 1H), 7.3 (m, 4H), 6.35(s, 1H), 4.8 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4-3.2 (m, 3H),3.05-2.9 (m, 1H), 2.6-2.3 (m, 3H), 2.2 (m, 1H), 1.9-1.6 (m, 3H), 1.6-1.4(m, 2H)

EXAMPLE 74-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-phenylphenyl)ethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 1 was followed using2-bromo-4′-phenylacetophenone as a reactant, instead of2-bromoacetophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (m, 1H), 7.85 (m, 1H), 7.6-7.3 (m, 9H),6.35 (s, 1H), 5.3 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.8-3.4 (m, 4H),3.2-3.0 (m, 2H), 3.0-2.7 (m, 2H), 2.4-1.6 (m, 3H), 1.6-1.4 (m, 2H)

EXAMPLE 84-amino-5-chloro-N-[[1-[2-hydroxy-2-(2-methoxyphenyl)ethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 1 was followed using2-bromo-2′-methoxyacetophenone as a reactant, instead of2-bromoacetophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (m, 1H), 7.85 (m, 1H), 7.6 (m, 1H), 7.3(m, 1H), 7.0 (m, 1H), 6.9 (m, 1H), 6.35 (s, 1H), 5.25 (m, 1H), 4.4 (s,2H), 3.9 (s, 3H), 3.8 (s, 3H), 3.6 (m, 2H), 3.1-3.0 (m, 2H), 2.9-2.7 (m,4H), 1.9-1.7 (m, 3H), 1.7-1.4 (m, 2H)

EXAMPLE 94-amino-5-chloro-N-[[1-[2-hydroxy-2-(3-methoxyphenyl)ethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 1 was followed using2-bromo-3′-methoxyacetophenone as a reactant, instead of2-bromoacetophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (m, 1H), 7.85 (m, 1H), 7.3-7.2 (m, 1H),7.0-6.9 (m, 2H), 6.85 (m, 1H), 6.35 (s, 1H), 4.8 (m, 1H), 4.4 (s, 2H),3.9 (s, 3H), 3.8 (s, 3H), 3.4-3.2 (m, 3H), 3.0 (m, 1H), 2.6 (m, 2H), 2.4(m, 1H), 2.2 (m, 1H), 1.9-1.6 (m, 3H), 1.6-1.4 (m, 2H)

EXAMPLE 104-amino-5-chloro-N-[[1-[2-(3,4-dichlorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 1 was followed using2-bromo-3′,4′-dichloroacetophenone as a reactant, instead of2-bromoacetophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.5 (s, 1H), 7.45(m, 1H), 7.2 (m, 1H), 6.35 (s, 1H), 4.8 (m, 1H), 4.4 (s, 2H), 3.9 (s,3H), 3.4 (m, 2H), 3.3-3.2 (m, 1H), 3.0 (m, 1H), 2.6-2.3 (m, 3H), 2.2 (m,1H), 1.9-1.6 (m, 3H), 1.6-1.3 (m, 2H)

EXAMPLE 114-amino-5-chloro-N-[[1-[2-(2,4-difluorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 1 was followed using2-bromo-2′,4′-difluoroacetophenone as a reactant, instead of2-bromoacetophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.85 (m, 1H), 7.65 (m, 1H),7.0-6.7 (m, 2H), 6.35 (s, 1H), 5.3 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H),3.5 (m, 1H), 3.4 (m, 2H), 3.2 (m, 2H), 2.9-2.2 (m, 4H), 2.7-2.4 (m, 2H),2.0-1.8 (m, 3H), 1.8-1.6 (m, 2H)

EXAMPLE 124-amino-N-[[1-[2-(4-tert-butylphenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-5-chloro-2-methoxybenzamide;hydrochloride

The procedure given in Example 1 was followed using2-bromo-4′-tert-butylacetophenone as a reactant, instead of2-bromoacetophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.45-7.3 (m, 4H),6.35 (s, 1H), 4.8 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4-3.2 (m, 3H),3.0 (m, 1H), 2.6 (m, 2H), 2.4 (m, 1H), 2.15 (m, 1H), 1.9-1.6 (m, 3H),1.55 (m, 2H), 1.3 (s, 9H)

EXAMPLE 134-amino-5-chloro-N-[[1-[2-(2-chlorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 1 was followed using2-bromo-2′-chloroacetophenone as a reactant, instead of2-bromoacetophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.85 (m, 1H), 7.75 (m, 1H), 7.3(m, 3H), 6.35 (s, 1H), 5.3 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4 (m,3H), 3.05 (m, 1H), 2.85 (m, 1H), 2.5 (m, 2H), 2.3 (m, 1H), 1.9-1.7 (m,3H), 1.6 (m, 2H)

EXAMPLE 144-amino-5-chloro-N-[[1-[2-(2,4-dimethylphenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 1 was followed using2-bromo-2′,4′-dimethylacetophenone as a reactant, instead of2-bromoacetophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.45 (m, 1H), 7.05(m, 1H), 6.95 (m, 1H), 6.35 (m, 1H), 5.05 (m, 1H), 4.4 (s, 2H), 3.9 (s,3H), 3.4-3.3 (m, 3H), 3.0 (m, 1H), 2.6-2.4 (m 3H), 2.35 (m, 6H), 2.2 (m,1H), 1.9-1.6 (m, 3H), 1.55 (m, 2H)

EXAMPLE 154-amino-5-chloro-N-[[1-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 1 was followed using2-bromo-2′,5′-dimethoxyacetophenone as a reactant, instead of2-bromoacetophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.2 (m, 1H), 6.8 (s,2H), 6.35 (m, 1H), 5.2 (m, 1H), 4.45 (s, 2H), 3.9 (s, 3H), 3.8 (m, 6H),3.35 (m, 2H), 3.0 (m, 1H), 2.8 (m, 1H), 2.55 (m 2H), 2.2 (m, 1H),1.9-1.7 (m, 3H), 1.5 (m 2H)

EXAMPLE 164-amino-5-chloro-N-[[1-[2-[4-(difluoromethoxy)phenyl]-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 1 was followed using2-bromo-4′-(difluoromethoxy)acetophenone as a reactant, instead of2-bromoacetophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.4 (m, 2H), 7.1 (m,2H), 6.35 (m, 1H), 4.85 (m, 1H), 4.45 (s, 2H), 3.9 (s, 3H), 3.4-3.2 (m,3H), 3.0 (m, 1H), 2.7-2.4 (m, 3H), 2.2 (m 1H), 1.9-1.7 (m, 3H), 1.5 (m2H)

EXAMPLE 174-amino-5-chloro-N-[[1-[2-(3,4-difluorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 1 was followed using2-bromo-3′,4′-difluoroacetophenone as a reactant, instead of2-bromoacetophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.3-7.1 (m, 3H),6.35 (m, 1H), 4.85 (m, 1H), 4.45 (s, 2H), 3.9 (s, 3H), 3.5-3.2 (m, 3H),3.0 (m, 1H), 2.7-2.4 (m, 3H), 2.2 (m 1H), 1.9-1.7 (m, 3H), 1.5 (m 2H)

EXAMPLE 184-amino-5-chloro-N-[[1-[2-hydroxy-2-[4-(trifluoromethyl)phenyl]ethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 1 was followed using2-bromo-4′-(trifluoromethyl)acetophenone as a reactant, instead of2-bromoacetophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.6 (m, 2H), 7.5 (m,2H), 6.35 (m, 1H), 4.9 (m, 1H), 4.45 (s, 2H), 3.9 (s, 3H), 3.4 (m, 2H),3.3 (m, 1H), 3.0 (m, 1H), 2.7-2.3 (m, 3H), 2.2 (m 1H), 1.9-1.7 (m, 3H),1.5 (m 2H)

EXAMPLE 194-amino-5-chloro-N-[[1-[2-(2,4-dichlorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 1 was followed using2-bromo-2′,4′-dichloroacetophenone as a reactant, instead of2-bromoacetophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.65 (m, 2H), 7.35(m, 2H), 6.35 (m, 1H), 5.25 (m, 1H), 4.45 (s, 2H), 3.9 (s, 3H), 3.4 (m,2H), 3.0 (m, 1H), 2.8 (m, 1H), 2.6-2.2 (m, 3H), 1.9-1.7 (m, 3H), 1.5 (m2H)

EXAMPLE 204-amino-5-chloro-N-[[1-[(2S)-2-hydroxy-2-phenylethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

A mixture of4-amino-5-chloro-2-methoxy-N-((piperidin-4-yl)methyl)benzamide (5.0mmol), (S)-styrene oxide (6.0 mmol) was refluxed in 30 ml of isopropanolfor 4 h. This solution was then concentrated on a rotary evaporator anddiluted with ethyl acetate. This mixture was then washed with brine, andthe resulting organic layer was dried and purified by columnchromatography. The resulting4-amino-5-chloro-N-[[1-[(2S)-2-hydroxy-2-phenylethyl]piperidin-4-yl]methyl]-2-methoxybenzamidewas dissolved in MC and the solution treated with a solution of HCl inether. The resulting precipitate was filtered to give the titlecompound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (m, 1H), 8.0-7.9 (br, 1H), 7.5-7.3 (m,5H), 6.35 (s, 1H), 5.45 (br, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.5-2.7 (m,6H), 2.2-2.0 (m, 2H), 1.9-1.4 (m, 5H)

EXAMPLE 214-amino-5-chloro-N-[[1-[(2R)-2-hydroxy-2-phenylethyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 20 was followed using (R)-styrene oxideas a reactant, instead of (S)-styrene oxide, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (, 1H), 8.0-7.9 (br, 1H), 7.5-7.3 (m, 5H),6.35 (s, 1H), 5.2 (br, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.5-2.7 (m, 6H),2.2-2.0 (m, 2H), 1.9-1.4 (m, 5H)

EXAMPLE 22[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-phenylethyl]carbamate;hydrochloride

4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidin-4-yl]methyl]-2-methoxybenzamide(1.5 mmol) from Example 1 was dissolved in 10 mL of THF and added with1,1′-carbonyl diimidazole (12 mmol) at 0° C. The reaction mixture wasstirred at room temperature for 2 h, followed by the addition of excessammonium hydroxide (3 ml) at room temperature. After 2 h stirring atroom temperature, water was added to terminate the reaction. The organiclayer was extracted 3 times with dichloromethane, dried, andconcentrated in vacuo. The resulting carbamate was dissolved in MC andthe solution treated with a solution of HCl in ether. The resultingprecipitate was filtered to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.2 (m, 5H), 6.35(s, 1H), 5.9 (m, 1H), 4.7 (m, 2H), 4.4 (s, 2H), 3.9 (m, 3H), 3.3 (m,2H), 3.1-2.8 (m, 3H), 2.6-2.5 (m, 1H), 2.2-2.0 (m, 2H), 1.8-1.3 (m, 5H)

EXAMPLE 23[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-fluorophenyl)ethyl]carbamate;hydrochloride

The procedure given in Example 22 was followed using4-amino-5-chloro-N-[[1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 2 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.2 (m, 2H),7.15-7.0 (m, 2H), 6.35 (s, 1H), 5.9-5.8 (m, 1H), 5.1-4.8 (br, 2H), 4.4(s, 2H), 3.9 (m, 3H), 3.4 (m, 2H), 3.3-3.0 (m, 3H), 2.8-2.6 (m, 2H),2.5-2.3 (m, 2H), 1.9-1.5 (m, 5H)

EXAMPLE 24[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-methylphenyl)ethyl]carbamate;hydrochloride

The procedure given in Example 22 was followed using4-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-methylphenyl)ethyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 3 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.3-7.1 (m, 4H), 6.35(s, 1H), 5.9-5.8 (m, 1H), 4.9 (m, 2H), 4.4 (s, 2H), 3.9 (m, 3H), 3.4 (m,2H), 3.2-2.9 (m, 3H), 2.6 (m, 1H), 2.35 (s, 3H), 2.3-2.1 (m, 2H),1.9-1.5 (m, 5H)

EXAMPLE 25[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-cyanophenyl)ethyl]carbamate;hydrochloride

The procedure given in Example 22 was followed using4-amino-5-chloro-N-[[1-[2-(4-cyanophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 5 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.7 (m, 2H), 7.5 (m,2H), 6.35 (s, 1H), 5.9-5.8 (m, 1H), 5.0-4.8 (br, 2H), 4.4 (s, 2H), 3.9(m, 3H), 3.4 (m, 2H), 3.1-2.9 (m, 3H), 2.7-2.6 (m, 1H), 2.4-2.2 (m, 2H),1.9-1.7 (m, 3H), 1.5 (m, 2H)

EXAMPLE 26[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-phenylphenyl)ethyl]carbamate;hydrochloride

The procedure given in Example 22 was followed using4-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-phenylphenyl)ethyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 7 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (DMSO-d6, 200 MHz) δ10.2 (br, 1H), 8.05 (s, 1H), 7.7 (m, 5H),7.5-7.3 (m, 4H), 6.9-6.8 (m, 2H), 6.5 (s, 1H), 6.05 (m, 1H), 3.9 (s,3H), 3.6 (m, 2H), 3.4 (m, 3H), 3.2 (m, 1H), 3.0 (m, 2H), 1.9-1.4 (m, 5H)

EXAMPLE 27[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(3-methoxyphenyl)ethyl]carbamate;hydrochloride

The procedure given in Example 22 was followed using4-amino-5-chloro-N-[[1-[2-hydroxy-2-(3-methoxyphenyl)ethyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 9 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (DMSO-d6, 200 MHz) δ10.1 (br, 1H), 8.05 (s, 1H), 7.65 (m, 1H),7.4-7.3 (m, 1H), 7.0-6.8 (m, 5H), 6.5 (s, 1H), 6.0 (m, 1H), 3.9 (s, 3H),3.85 (s, 3H), 3.6 (m, 2H), 3.4 (m, 3H), 3.2 (m, 1H), 3.0 (m, 2H),1.9-1.4 (m, 5H)

EXAMPLE 28[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(3,4-dichlorophenyl)ethyl]carbamate;hydrochloride

The procedure given in Example 22 was followed using4-amino-5-chloro-N-[[1-[2-(3,4-dichlorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 10 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.85 (m, 1H), 7.5 (m, 2H), 7.3(m, 1H), 6.35 (s, 1H), 5.95 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4 (m,2H), 3.3-3.0 (m, 3H), 2.7 (m, 1H), 2.6-2.3 (m, 2H), 1.9-1.6 (m, 5H)

EXAMPLE 29[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(2-chlorophenyl)ethyl]carbamate;hydrochloride

The procedure given in Example 22 was followed using4-amino-5-chloro-N-[[1-[2-(2-chlorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 13 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.5-7.2 (m, 4H),6.35 (m, 1H), 6.3 (m, 1H), 5.1 (m, 2H), 4.45 (s, 2H), 3.9 (s, 3H),3.4-3.2 (m, 3H), 3.0 (m, 1H), 2.9 (m 1H), 2.7 (m, 1H), 2.3 (m, 2H),1.9-1.6 (m, 3H), 1.55 (m, 2H)

EXAMPLE 30[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(2,4-dimethylphenyl)ethyl]carbamate;hydrochloride

The procedure given in Example 22 was followed using4-amino-5-chloro-N-[[1-[2-(2,4-dimethylphenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 14 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.05 (m, 1H), 7.0(m, 2H), 6.35 (s, 1H), 6.1 (m, 1H), 4.9 (br, 2H), 4.45 (s, 2H), 3.9 (s,3H), 3.4 (m, 2H), 3.2 (m, 1H), 3.05-2.9 (m, 2H), 2.6 (m, 2H), 2.5-2.1(m, 7H), 1.9-1.5 (m, 5H)

EXAMPLE 31[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(2,5-dimethoxyphenyl)ethyl]carbamate;hydrochloride

The procedure given in Example 22 was followed using4-amino-5-chloro-N-[[1-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 15 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 6.95 (s, 1H), 6.8(s, 2H), 6.35 (s, 1H), 6.3 (m, 1H), 4.95 (br, 2H), 4.45 (s, 2H), 3.9 (s,3H), 3.8 (d, 6H), 3.4-3.2 (m, 3H), 3.0 (m, 1H), 2.9 (m, 1H), 2.7 (m,1H), 2.4-2.2 (m, 2H), 1.9-1.7 (m, 3H), 1.5 (m 2H)

EXAMPLE 32[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-[4-(difluoromethoxy)phenyl]ethyl]carbamate;hydrochloride

The procedure given in Example 22 was followed using4-amino-5-chloro-N-[[1-[2-[4-(difluoromethoxy)phenyl]-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 16 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.4 (m, 2H), 7.15(m, 2H), 6.65 (s, 1H), 6.35 (s, 1H), 5.9 (m, 1H), 5.1-4.8 (br, 2H), 4.45(s, 2H), 3.9 (s, 3H), 3.4-3.2 (m, 2H), 3.3-3.0 (m, 3H), 2.7 (m, 1H),2.5-2.2 (m, 2H), 1.9-1.5 (m, 5H)

EXAMPLE 33[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(3,4-difluorophenyl)ethyl]carbamate;hydrochloride

The procedure given in Example 22 was followed using4-amino-5-chloro-N-[[1-[2-(3,4-difluorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 17 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.3-7.0 (m, 3H),6.35 (s, 1H), 5.8 (m, 1H), 5.1-4.8 (br, 2H), 4.4 (s, 2H), 3.9 (s, 3H),3.35 (m, 2H), 3.2-2.9 (m, 2H), 2.6 (m, H), 2.4-2.1 (m, 3H), 1.9-1.4 (m,5H)

EXAMPLE 34[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-[4-(trifluoromethyl)phenyl]ethyl]carbamate;hydrochloride

The procedure given in Example 22 was followed using4-amino-5-chloro-N-[[1-[2-hydroxy-2-[4-(trifluoromethyl)phenyl]ethyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 18 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.65 (m, 2H), 7.5(m, 2H), 6.35 (s, 1H), 5.9 (m, 1H), 5.1-4.8 (br, 2H), 4.4 (s, 2H), 3.9(s, 3H), 3.35 (m, 2H), 3.2-2.9 (m, 3H), 2.6 (m, H), 2.4-2.1 (m, 2H),1.9-1.4 (m, 5H)

EXAMPLE 35[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(2,4-dichlorophenyl)ethyl]carbamate;hydrochloride

The procedure given in Example 22 was followed using4-amino-5-chloro-N-[[1-[2-(2,4-dichlorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 19 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.5-7.2 (m, 3H),6.35 (s, 1H), 6.2 (m, 1H), 5.1-4.8 (br, 2H), 4.4 (s, 2H), 3.9 (s, 3H),3.35 (m, 2H), 3.2 (m, 1H), 3.0 (m, 1H), 2.8 (m, 1H), 2.65 (m, 1H), 2.35(m, 2H), 1.9-1.4 (m, 5H)

EXAMPLE 364-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

A mixture of4-amino-5-chloro-2-methoxy-N-((piperidin-4-yl)methyl)benzamide (5.0mmol), 3-chloropropiophenone (6.0 mmol), potassium carbonate (7.6 mmol),and potassium iodide (7.6 mmol) was refluxed in 15 mL of acetonitrilefor 12 h. This solution was then concentrated on a rotary evaporator anddiluted with ethyl acetate. This mixture was then washed with brine, andthe resulting organic layer was dried and purified by columnchromatography. This was dissolved in ethanol (10 mL) and was added withsodium borohydride (10.0 mmol) at 0° C. and stirred at 25° C. for 2 h.This solution was concentrated on a rotary evaporator and diluted withethylacetate. This mixture was washed with brine, dried, andconcentrated in vacuo. The residue was purified by columnchromatography. The resulting4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamidewas dissolved in MC and the solution treated with a solution of HCl inether. The resulting precipitate was filtered to give the titlecompound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.4-7.2 (m, 5H),6.35 (s, 1H), 4.95 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4-3.1 (m, 4H),2.75 (m, 2H), 2.3-1.7 (m, 7H), 1.5 (m, 2H)

EXAMPLE 374-amino-5-chloro-N-[[1-[3-(4-fluorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 36 was followed using3-chloro-4′-fluoropropiophenone as a reactant, instead of3-chloropropiophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.3 (m, 2H),7.1-7.0 (m, 2H), 6.35 (s, 1H), 4.9 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H),3.4-3.1 (m, 4H), 2.9-2.7 (m, 2H), 2.4-2.0 (m, 2H), 1.9-1.7 (m, 5H),1.7-1.5 (m, 2H)

EXAMPLE 384-amino-5-chloro-N-[[1-[3-(4-chlorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 36 was followed using3-chloro-4′-chloropropiophenone as a reactant, instead of3-chloropropiophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.4-7.35 (m, 2H),7.1-6.9 (m, 2H), 6.35 (s, 1H), 4.9 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H),3.4 (m, 2H), 3.3-3.1 (m, 2H), 2.8-2.6 (m, 2H), 2.3-1.7 (m, 7H), 1.5 (m,2H)

EXAMPLE 394-amino-5-chloro-N-[[1-[3-hydroxy-3-(4-methylphenyl)propyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 36 was followed using3-chloro-4′-methylpropiophenone as a reactant, instead of3-chloropropiophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (m, 1H), 7.85 (m, 1H), 7.3 (m, 2H), 7.2(m, 2H), 6.35 (s, 1H), 4.95 (t, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4 (m,2H), 3.2 (m, 2H), 2.8-2.7 (m, 2H), 2.4 (s, 3H), 2.2 (m, 1H), 2.05-1.7(m, 6H), 1.4-1.2 (m, 2H)

EXAMPLE 404-amino-5-chloro-N-[[1-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 36 was followed using3-chloro-4′-methoxypropiophenone as a reactant, instead of3-chloropropiophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (m, 1H), 7.85 (m, 1H), 7.3 (m, 2H), 6.9(m, 2H), 6.35 (s, 1H), 4.95 (t, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.8 (s,3H), 3.4 (m, 2H), 3.3-3.1 (m, 2H), 2.8-2.6 (m, 2H), 2.2 (m, 1H), 2.2-1.7(m, 6H), 1.6-1.4 (m, 2H)

EXAMPLE 414-amino-5-chloro-N-[[1-[3-(2-chlorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

A mixture of 2-chlorobenzoic acid (5 mmol) and 1,1′-carbonyl diimidazolewas stirred in 30 ml of THF for 30 min, and N,O-dimethylhydroxylaminehydrochloride (6.5 mmol) and triethylamine (5 mmol) were added. After 12h stirring at room temperature, water was added to terminate thereaction. The organic layer was extracted 2 times with ethylacetate andthe organic layer was washed with 5% HCl solution and brine, dried, andconcentrated in vacuo. The crude product was dissolved in THF (30 ml)and added with 1M solution of vinylmagnesium bromide (5.5 mmol) in THFat 0° C. After 10 min stirring, the mixture was warmed to roomtemperature and stirred for 1 h, followed by the addition of4-amino-5-chloro-2-methoxy-N-((piperidin-4-yl)methyl)benzamide (7.5mmol) and water (7.5 ml) at room temperature. After 30 min stirring atroom temperature, water and ethylacetate added and organic layer waswashed with brine, dried, and concentrated in vacuo. The residue waspurified by column chromatography. This was dissolved in ethanol (10 mL)and was added with sodium borohydride (10.0 mmol) at 0° C. and stirredat 25° C. for 2 h. This solution was concentrated on a rotary evaporatorand diluted with ethylacetate. This mixture was washed with brine,dried, and concentrated in vacuo. The resulting4-amino-5-chloro-N-[[1-[3-(2-chlorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidewas dissolved in MC and the solution treated with a solution of HCl inether. The resulting precipitate was filtered to give the titlecompound.

1H-NMR (CDCl3, 200 MHz) δ8.05 (s, 1H), 7.8 (m, 1H), 7.7 (m, 1H), 7.4-7.1(m, 3H), 5.3 (s, 1H), 4.5 (s, 2H), 3.9 (s, 3H), 3.35 (m, 2H), 3.1 (m,2H), 2.6 (m, 2H), 2.2-1.6 (m, 7H), 1.5-1.3 (m, 2H)

EXAMPLE 424-amino-5-chloro-N-[[1-[3-(3-chlorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 41 was followed using 3-chlorobenzoicacid as a reactant, instead of 2-chlorobenzoic acid, to give the titlecompound.

1H-NMR (CDCl3, 200 MHz) δ 8.05 (s, 1H), 7.8 (m, 1H), 7.4 (s, 1H),7.3-7.1 (m, 3H), 6.3 (s, 1H), 4.9 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H),3.35 (m, 2H), 3.1 (m, 2H), 2.6 (m, 2H), 2.1-1.9 (m, 1H), 1.9-1.5 (m,6H), 1.5-1.3 (m, 2H)

EXAMPLE 434-amino-5-chloro-N-[[1-[3-(2-fluorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 41 was followed using 2-fluorobenzoicacid as a reactant, instead of 2-chlorobenzoic acid, to give the titlecompound.

1H-NMR (CDCl3, 200 MHz) δ8.05 (s, 1H), 7.8 (m, 1H), 7.6 (m, 1H), 7.2 (m,2H), 6.95 (m, 1H), 6.3 (s, 1H), 5.2 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H),3.3 (m, 2H), 3.1 (m, 2H), 2.6 (m, 2H), 2.2-1.5 (m, 7H), 1.5-1.1 (m, 2H)

EXAMPLE 444-amino-5-chloro-N-[[1-[3-(3-fluorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 41 was followed using 3-fluorobenzoicacid as a reactant, instead of 2-chlorobenzoic acid, to give the titlecompound.

1H-NMR (CDCl3, 200 MHz) δ8.05 (s, 1H), 7.8 (m, 1H), 7.3 (m, 1H), 7.1 (m,2H), 6.9 (m, 1H), 6.3 (s, 1H), 4.9 (m, 1H), 4.6 (s, 2H), 3.9 (s, 3H),3.3 (m, 2H), 3.1 (m, 2H), 2.6 (m, 2H), 2.2-1.5 (m, 7H), 1.5-1.2 (m, 2H)

EXAMPLE 454-amino-5-chloro-N-[[1-[3-(2,3-dichlorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 41 was followed using 2,3-dichlorobenzoicacid as a reactant, instead of 2-chlorobenzoic acid, to give the titlecompound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.6 (m, 1H), 7.3 (m,4H), 6.35 (s, 1H), 5.2 (m, 1H), 4.5 (m, 2H), 3.9 (s, 3H), 3.35 (m, 2H),3.1 (m, 2H), 2.8-2.5 (m, 2H), 2.2-1.6 (m, 7H), 1.4 (m, 2H)

EXAMPLE 464-amino-5-chloro-N-[[1-[3-(2,4-dichlorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 41 was followed using 2,4-dichlorobenzoicacid as a reactant, instead of 2-chlorobenzoic acid, to give the titlecompound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.6 (m, 1H), 7.4-7.2(m, 2H), 6.35 (s, 1H), 5.3 (m, 1H), 4.5 (s, 2H), 3.9 (s, 3H), 3.35 (m,2H), 3.1 (m, 2H), 2.8-2.5 (m, 2H), 2.2-1.6 (m, 7H), 1.4 (m, 2H)

EXAMPLE 474-amino-5-chloro-N-[[1-[3-(3,4-dichlorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 41 was followed using 3,4-dichlorobenzoicacid as a reactant, instead of 2-chlorobenzoic acid, to give the titlecompound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.5-7.3 (m, 2H), 7.2(m, 1H), 6.35 (s, 1H), 4.95 (m, 1H), 4.5 (s, 2H), 3.9 (s, 3H), 3.35 (m,2H), 3.2 (m, 2H), 2.8-2.6 (m, 2H), 2.2-1.6 (m, 7H), 1.5 (m, 2H)

EXAMPLE 484-amino-5-chloro-N-[[1-[3-(4-isopropylphenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 41 was followed using 4-isopropylbenzoicacid as a reactant, instead of 2-chlorobenzoic acid, to give the titlecompound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.3-7.15 (m, 4H), 7.2(m, 2H), 6.3 (s, 1H), 4.9 (m, 1H), 4.5 (s, 2H), 3.9 (s, 3H), 3.35 (m,2H), 3.2 (m, 2H), 2.9 (m, 1H), 2.6 (m, 2H), 2.2-1.6 (m, 7H), 1.4 (m,2H), 1.3 (m, 6H)

EXAMPLE 494-amino-5-chloro-N-[[1-[3-(3-methoxyphenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 41 was followed using 3-methoxybenzoicacid as a reactant, instead of 2-chlorobenzoic acid, to give the titlecompound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.3-7.2 (m, 1H), 6.9(m, 2H), 6.8 (m, 1H), 6.3 (s, 1H), 5.7 (br, 1H), 4.9 (m, 1H), 4.55 (s,2H), 3.9 (s, 3H), 3.85 (s, 3H), 3.3 (m, 2H), 3.1 (m, 2H), 2.65 (m, 2H);2.1 (m, 2H), 2.0 (m, 1H), 1.9-1.6 (m, 3H), 1.45 (m, 2H)

EXAMPLE 504-amino-5-chloro-N-[[1-(3-hydroxy-3-thiophen-2-ylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 41 was followed using2-thiophenecarboxylic acid as a reactant, instead of 2-chlorobenzoicacid, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.3-7.2 (m, 1H), 6.9(m, 2H), 6.8 (m, 1H), 6.3 (s, 1H), 5.2 (m, 1H), 4.9 (br, 1H), 4.55 (s,2H), 3.9 (s, 3H), 3.35 (m, 2H), 3.2 (m, 2H), 2.7 (m, 2H), 2.2 (m, 1H),2.1 (m, 3H), 1.9-1.6 (m, 3H), 1.45 (m, 2H)

EXAMPLE 514-amino-5-chloro-N-[[1-[4-(4-fluorophenyl)-3-hydroxybutyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 41 was followed using4-fluorophenylacetic acid as a reactant, instead of 2-chlorobenzoicacid, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.2 (m, 2H), 7.0 (m,2H), 6.3 (s, 1H), 4.4 (s, 2H), 4.0 (m, 1H), 3.9 (s, 3H), 3.3 (m, 2H),3.0 (m, 1H), 2.9-2.6 (m, 4H), 2.3-1.3 (m, 11H)

EXAMPLE 524-amino-5-chloro-N-[[1-[5-(4-fluorophenyl)-3-hydroxypentyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 41 was followed using3-(4-fluorophenyl)propionic acid as a reactant, instead of2-chlorobenzoic acid, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.75 (m, 1H), 7.15 (m, 2H), 7.0(m, 2H), 6.3 (s, 1H), 4.4 (s, 2H), 3.85 (s, 3H), 3.8 (m, 4H), 3.3 (m,H), 3.2 (m, 1H), 3.0-2.6 (m, 6H), 2.1 (m, 1H), 2.0-1.6 (m, 4H), 1.6-1.3(m, 2H)

EXAMPLE 53[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-phenylpropyl]carbamate;hydrochloride

4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide(1.5 mmol) from Example 34 was dissolved in 10 mL of THF and added with1,1′-carbonyl diimidazole (12 mmol) at 0° C. The reaction mixture wasstirred at room temperature for 4 h, followed by the addition of excessammonium hydroxide (3 ml) at 0° C. After 2 h stirring at roomtemperature, water was added to terminate the reaction. The organiclayer was extracted 3 times with dichloromethane, dried, andconcentrated in vacuo. The resulting carbamate was dissolved indichloromethane and the solution treated with a solution of HCl inether. The resulting precipitate was filtered to give the titlecompound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.75 (m, 1H), 7.4-7.3 (m, 5H),6.3 (s, 1H), 5.7 (m, 1H), 4.6 (m, 2H), 4.4 (s, 2H), 3.9 (s, 3H), 3.35(m, 2H), 2.9 (m, 2H), 2.4-2.3 (m, 2H), 2.0-1.8 (m, 2H), 1.8-1.5 (m, 3H),1.4-1.2 (m, 2H)

EXAMPLE 54[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-fluorophenyl)propyl]carbamate;hydrochloride

The procedure given in Example 53 was followed using4-amino-5-chloro-N-[[1-[3-(4-fluorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 35 as a reactant, instead of4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.2 (m, 2H),7.1-7.0 (m, 2H), 6.35 (s, 1H), 5.7 (m, 1H), 4.6 (m, 2H), 4.4 (s, 2H),3.9 (s, 3H), 3.4-3.2 (m, 2H), 3.0-2.8 (m, 2H), 2.4-2.1 (m, 4H), 2.0-1.5(m, 5H), 1.5-1.3 (m, 2H)

EXAMPLE 55[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-chlorophenyl)propyl]carbamate;hydrochloride

The procedure given in Example 53 was followed using4-amino-5-chloro-N-[[1-[3-(4-chlorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 36 as a reactant, instead of4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.4-7.2 (m, 2H),7.1-7.0 (m, 2H), 6.35 (s, 1H), 5.7 (m, 1H), 4.7 (m, 2H), 4.4 (s, 2H),3.9 (s, 3H), 3.4 (m, 2H), 3.1-2.9 (m, 2H), 2.4 (m, 2H), 2.3-1.6 (m, 7H),1.5-1.3 (m, 2H)

EXAMPLE 56[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(2-chlorophenyl)propyl]carbamate;hydrochloride

The procedure given in Example 53 was followed using4-amino-5-chloro-N-[[1-[3-(2-chlorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 39 as a reactant, instead of4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.5-7.1 (m, 4H), 6.3(s, 1H), 6.05 (m, 1H), 5.0 (m, 2H), 4.5 (m, 2H), 3.9 (s, 3H), 3.3 (m,2H), 3.0 (m, 2H), 2.55 (m, 2H), 2.1 (m, 2H), 1.8-1.2 (m, 5H), 0.9 (m,2H)

EXAMPLE 57[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(2-fluorophenyl)propyl]carbamate;hydrochloride

The procedure given in Example 53 was followed using4-amino-5-chloro-N-[[1-[3-(2-fluorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 41 as a reactant, instead of4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.4-6.9 (m, 4H), 6.3(s, 1H), 5.95 (m, 1H), 5.0 (s, 2H), 4.5 (m, 2H), 3.85 (s, 3H), 3.3 (m,2H), 2.95 (m, 2H), 2.45 (m, 2H), 2.1 (m, 2H), 1.8-1.2 (m, 5H), 0.9 (m,2H)

EXAMPLE 58[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(3-fluorophenyl)propyl]carbamate;hydrochloride

The procedure given in Example 53 was followed using4-amino-5-chloro-N-[[1-[3-(3-fluorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 42 as a reactant, instead of4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.3 (m, 1H), 7.1-6.9(m, 3H), 6.3 (s, 1H), 5.65 (m, 1H), 4.9 (s, 2H), 4.5 (s, 2H), 3.85 (s,3H), 3.3 (m, 2H), 2.9 (m, 2H), 2.35 (m, 2H), 2.2-1.8 (m, 2H), 1.8-1.2(m, 5H), 0.9 (m, 2H)

EXAMPLE 59[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(2,3-dichlorophenyl)propyl]carbamate;hydrochloride

The procedure given in Example 53 was followed using4-amino-5-chloro-N-[[1-[3-(2,3-dichlorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 43 as a reactant, instead of4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.15 (m, 3H), 6.3(s, 1H), 6.05 (m, 1H), 5.05 (m, 2H), 4.5 (s, 2H), 3.9 (s, 3H), 3.3 (m,2H), 2.95 (m, 2H), 2.5 (m, 2H), 2.1-1.8 (m, 4H), 1.8-1.5 (m, 3H), 1.3(m, 2H)

EXAMPLE 60[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(2,4-dichlorophenyl)propyl]carbamate;hydrochloride

The procedure given in Example 53 was followed using4-amino-5-chloro-N-[[1-[3-(2,4-dichlorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 44 as a reactant, instead of4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.15 (m, 3H), 6.3(s, 1H), 6.05 (m, 1H), 5.05 (br, 2H), 4.5 (s, 2H), 3.9 (s, 3H), 3.35 (m,2H), 3.05 (m, 2H), 2.6 (m, 2H), 2.1-1.8 (m, 4H), 1.8-1.5 (m, 3H), 1.3(m, 2H)

EXAMPLE 61[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(3,4-dichlorophenyl)propyl]carbamate;hydrochloride

The procedure given in Example 53 was followed using4-amino-5-chloro-N-[[1-[3-(3,4-dichlorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 45 as a reactant, instead of4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.45 (m, 2H), 7.2 (m,1H), 6.3 (s, 1H), 5.6 (m, 1H), 4.95 (br, 2H), 4.45 (s, 2H), 3.9 (s, 3H),3.53 (m, 2H), 2.9 (m, 2H), 2.3 (m, 4H), 2.2-1.5 (m, 5H), 1.3 (m, 2H)

EXAMPLE 62[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-isopropylphenyl)propyl]carbamate;hydrochloride

The procedure given in Example 53 was followed using4-amino-5-chloro-N-[[1-[3-(4-isopropylphenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 46 as a reactant, instead of4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.3-7.1 (m, 4H), 6.3(s, 1H), 5.65 (s, 1H), 4.95 (s, 2H), 4.5 (s, 2H), 3.85 (s, 3H), 3.3 (m,2H), 3.1-2.8 (m, 3H), 2.4 (m, 2H), 2.2-1.8 (m, 4H), 1.8-1.5 (m, 3H),1.4-1.2 (m, 8H)

EXAMPLE 63[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(3-methoxyphenyl)propyl]carbamate;hydrochloride

The procedure given in Example 53 was followed using4-amino-5-chloro-N-[[1-[3-(3-methoxyphenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 47 as a reactant, instead of4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.25 (m, 1H), 6.9 (m,3H), 6.3 (s, 1H), 5.7 (m, 1H), 4.9 (s, 2H), 4.55 (s, 2H), 3.9 (s, 3H),3.8 (s, 3H), 3.35 (m, 2H), 2.95 (m, 2H), 2.4 (m, 2H), 2.2-1.9 (m, 4H),1.8-1.5 (m, 3H), 1.45-1.2 (m, 2H)

EXAMPLE 64[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-thiophen-2-ylpropyl]carbamate;hydrochloride

The procedure given in Example 53 was followed using4-amino-5-chloro-N-[[1-(3-hydroxy-3-thiophen-2-ylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 48 as a reactant, instead of4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.3 (m, 1H), 7.1-6.9(m, 2H), 6.35 (s, 1H), 4.75 (s, 2H), 4.4 (s, 2H), 3.9 (s, 3H), 3.35 (m,2H), 3.1 (m, 2H), 2.55 (m, 1H), 2.5-2.0 (m, 5H), 1.9-1.2 (m, 5H)

EXAMPLE 65[4-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-fluorophenyl)butan-2-yl]carbamate;hydrochloride

The procedure given in Example 53 was followed using4-amino-5-chloro-N-[[1-[4-(4-fluorophenyl)-3-hydroxybutyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 51 as a reactant, instead of4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.75 (m, 1H), 7.15 (m, 2H), 7.0(m, 2H), 6.3 (s, 1H), 4.9 (m, 1H), 4.8 (s, 2H), 4.5 (s, 2H), 3.85 (s,3H), 3.3 (m, 2H), 2.9-2.8 (m, 4H), 2.4 (m, 2H), 1.9 (m, 2H), 1.8-1.5 (m,5H), 1.3 (m, 2H)

EXAMPLE 66[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-5-(4-fluorophenyl)pentan-3-yl]carbamatehydrochloride

The procedure given in Example 53 was followed using4-amino-5-chloro-N-[[1-[5-(4-fluorophenyl)-3-hydroxypentyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 52 as a reactant, instead of4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.75 (m, 1H), 7.15 (m, 2H), 6.95(m, 2H), 6.3 (s, 1H), 4.8 (m, 1H), 4.75 (s, 2H), 4.45 (s, 2H), 3.85 (s,3H), 3.35 (m, 2H), 2.95 (m, 2H), 2.65 (m, 2H), 2.4 (m, 2H), 2.0-1.5 (m,9H), 1.3 (m, 2H)

EXAMPLE 67(S)-4-amino-5-chloro-N-[[1-[3-(4-fluorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

A solution of 3-Chloro-4′-fluoropropiophenone (5.4 mmol) was slowlyadded to 1.6M solution of (−)-chlorodiisopinocampheylborane in Hexane(8.1 mmol) at −25° C. This reaction mixture was stirred at roomtemperature for 16 h. After 16 h stirring at −25° C., MeOH was added toterminate the reaction, then it was washed with brine, and the resultingorganic layer was dried and concentrated in vacuo. The crude product wasdissolved in 20 mL of acetonitrile and was added4-amino-5-chloro-2-methoxy-N-[(piperidin-4-yl)methyl]benzamide (3.6mmol), potassium carbonate (5.4 mmol), and potassium iodide (5.4 mmol)at 25° C. The reaction mixture was refluxed for 12 h. This solution wasthen concentrated on a rotary evaporator and diluted with ethylacetate,washed with brine, the resulting organic layer was dried and purified bycolumn chromatography. The resulting(S)-4-amino-5-chloro-N-[[1-[3-(4-fluorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidewas dissolved in MC and the solution treated with a solution of HCl inether. The resulting precipitate was filtered to give the titlecompound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.3 (m, 2H),7.1-7.0 (m, 2H), 6.35 (s, 1H), 4.9 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H),3.4-3.1 (m, 4H), 2.9-2.7 (m, 2H), 2.4-2.0 (m, 2H), 1.9-1.7 (m, 5H),1.7-1.5 (m, 2H)

EXAMPLE 68(S)-[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-fluorophenyl)propyl]carbamate;hydrochloride

(S)-4-amino-5-chloro-N-[[1-[3-(4-fluorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide(1.5 mmol) from Example 62 was dissolved in 10 mL of THF and added with1,1′-carbonyldiimidazole (12 mmol) at 0° C. The reaction mixture wasstirred at room temperature for 4 h, followed by the addition of excessammonium hydroxide (3 ml) at 0° C. After 2 h stirring at roomtemperature, water was added to terminate the reaction. The organiclayer was extracted 3 times with dichloromethane, dried, andconcentrated in vacuo. The resulting(S)-[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-fluorophenyl)propyl]carbamatewas dissolved in MC and the solution was treated with a solution of HClin ether. The resulting precipitate was filtered to give the titlecompound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.2 (m, 2H),7.1-7.0 (m, 2H), 6.3 (s, 1H), 5.7 (m, 1H), 4.6 (m, 2H), 4.4 (s, 2H), 3.9(s, 3H), 3.4-3.1 (m, 4H), 2.8-2.6 (m, 2H), 2.3-2.0 (m, 2H), 2.0-1.6 (m,5H), 1.5-1.3 (m, 2H)

EXAMPLE 69(R)-4-amino-5-chloro-N-[[1-[3-(4-fluorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 67 was followed using(+)-chlorodiisopinocampheylborane as a reactant, instead of(−)-chlorodiisopinocampheylborane, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.3 (m, 2H),7.1-7.0 (m, 2H), 6.35 (s, 1H), 4.9 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H),3.4-3.1 (m, 4H), 2.9-2.7 (m, 2H), 2.4-2.0 (m, 2H), 1.9-1.7 (m, 5H),1.7-1.5 (m, 2H)

EXAMPLE 70(R)-[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-fluorophenyl)propyl]carbamate;hydrochloride

The procedure given in Example 68 was followed using(R)-4-amino-5-chloro-N-[[1-[3-(4-fluorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamideas a reactant, instead of(S)-4-amino-5-chloro-N-[[1-[3-(4-fluorophenyl)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound

1H-NMR (CDCl3, 200 MHz) δ8.15 (m, 1H), 7.8 (m, 1H), 7.4-7.3 (m, 4H),6.35 (s, 1H), 4.9 (m, 2H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4 (m, 2H),3.3-3.1 (m, 2H), 2.7 (m, 2H), 2.2 (m, 1H), 2.1-1.6 (m, 6H), 1.5-1.3 (m,2H)

EXAMPLE 714-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

A mixture of4-amino-5-chloro-2-methoxy-N-[(piperidin-4-yl)methyl]benzamide (3 mmol)and 1,2-epoxy-3-phenoxypropane (3 mmol) was refluxed in 10 mL ofisopropanol for 3 h. This solution was concentrated on a rotaryevaporator and the mixture was purified by column chromatography. Theresulting4-amino-5-chloro-N-((1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl)methyl)-2-methoxybenzamidewas dissolved in MC and the solution treated with a solution of HCl inether. The resulting precipitate was filtered to give the titlecompound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.75 (br, 1H), 8.0 (m,1H), 7.66 (s, 1H), 7.30 (m, 2H), 6.96 (m, 3H), 6.48 (s, 1H), 5.96 (s,2H), 4.35 (m, 1H), 3.95 (m, 2H), 3.83 (m, 3H), 3.54 (m, 2H), 3.17 (m,4H), 3.0 (m, 2H), 1.9-1.5 (m, 5H)

EXAMPLE 724-amino-5-chloro-N-[[1-[3-(4-fluorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 71 was followed using 4-fluorophenylglycidyl ether as a reactant, instead of 1,2-epoxy-3-phenoxypropane, togive the title compound.

1H NMR (DMSO, 500 MHz), ppm (δ): (HCl salt form)

9.3 (m, 1H), 8.0 (s, 1H), 7.67 (s, 1H), 7.13 (m, 2H), 6.96 (m, 2H), 6.48(s, 1H), 5.93 (s, 2H), 4.3 (m, 1H), 3.92 (s, 2H), 3.83 (s, 3H), 3.55 (m,2H), 3.3-3.2 (m, 4H), 3.0 (m, 2H), 1.77 (m, 3H), 1.6 (m, 1H), 1.5 (m,1H)

EXAMPLE 734-amino-5-chloro-N-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 71 was followed using 4-chlorophenylglycidyl ether as a reactant, instead of 1,2-epoxy-3-phenoxypropane, togive the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (free amine form) 7.9 (m, 1H), 7.65 (s,1H), 7.3 (m, 2H), 6.95 (m, 2H), 6.46 (s, 1H), 5.93 (s, 2H), 4.85 (m,1H), 4.0-3.8 (m, 5H), 3.3-3.1 (m, 4H), 2.9 (m, 2H), 2.4 (m, 1H), 2.0 (m,2H), 1.7-1.4 (m, 3H), 1.2 (m, 2H)

EXAMPLE 744-amino-5-chloro-N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 71 was followed using glycidyl4-methoxyphenyl ether as a reactant, instead of1,2-epoxy-3-phenoxypropane, to give the title compound.

1H NMR (DMSO, 500 MHz), ppm (δ): (HCl salt form) 9.4 (m, 1H), 8.00 (m,1H), 7.67 (s, 1H), 6.86 (m, 4H), 6.48 (m, 1H), 5.91 (m, 2H), 4.29 (m,1H), 3.9) m, 2H), 3.83 (s, 3H), 3.52 (m, 2H), 3.21 (m, 4H), 2.90 (m,2H), 1.75 (m, 3H), 1.56 (m, 1H), 1.47 (m, 1H)

EXAMPLE 754-amino-5-chloro-N-[[1-[3-(2,3-dichlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 71 was followed using 2,3-dichlorophenylglycidyl ether as a reactant, instead of 1,2-epoxy-3-phenoxypropane, togive the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.9-7.85 (m, 1H), 7.25 (s, 1H),7.20-7.05 (m, 2H), 6.95 (m, 1H), 6.35 (s, 1H), 4.4 (m, 2H), 4.2 (m, 1H),4.05 (m, 2H), 3.9 (s, 3H), 3.3 (m, 2H), 3.1 (m, 1H), 3.0 (m, 1H), 2.7(m, 2H), 2.4 (m, 1H), 2.2 (m, 1H), 1.97-1.8 (m, 3H), 1.6-1.4 (m, 2H)

EXAMPLE 764-amino-5-chloro-N-[[1-[3-(2,4-dichlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 71 was followed using 2,4-dichlorophenylglycidyl ether as a reactant, instead of 1,2-epoxy-3-phenoxypropane, togive the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.9-7.85 (m, 1H), 7.4 (s, 1H),7.20 (m, 1H), 6.9 (m, 1H), 6.35 (s, 1H), 4.4 (m, 2H), 4.2 (m, 1H), 4.05(m, 2H), 3.9 (s, 3H), 3.4 (m, 2H), 3.1 (m, 1H), 2.9 (m, 1H), 2.65 (m,2H), 2.4 (m, 1H), 2.1 (m, 1H), 1.9-1.65 (m, 3H), 1.6-1.25 (m, 2H)

EXAMPLE 774-amino-5-chloro-N-[[1-[3-(2,5-dichlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 71 was followed using 2,5-dichlorophenylglycidyl ether as a reactant, instead of 1,2-epoxy-3-phenoxypropane, togive the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.3 (M, 1H), 6.95 (m,2H), 6.3 (s, 1H), 4.4 (s, 2H), 4.2 (m, 1H), 4.0 (m, 2H), 3.9 (s, 3H),3.4 (t, 2H), 3.1 (m, 1H), 2.9 (m, 1H), 2.6 (t, 2H), 2.4 (m, 1H), 2.1 (m,1H), 1.9-1.8 (m, 3H), 1.5-1.3 (m, 2H)

EXAMPLE 784-amino-5-chloro-N-[[1-[3-(2,6-dichlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 71 was followed using 2,6-dichlorophenylglycidyl ether as a reactant, instead of 1,2-epoxy-3-phenoxypropane, togive the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.8 (m, 1H), 8.1 (s, 1H), 7.3 (2H), 7.0 (t,1H), 6.35 (s, 1H), 4.4 (s, 2H), 4.2 (s, 1H), 4.1 (t, 2H), 3.95 (s, 3H),3.4 (t, 2H), 3.15 (m, 1H), 3.0 (m, 1H), 2.75 (m, 2H), 2.4 (m, 1H), 2.2(m, 1H), 1.8 (m, 3H), 1.6-1.3 (m, 2H)

EXAMPLE 794-amino-5-chloro-N-[[1-[3-(3,4-dichlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 71 was followed using 3,4-dichlorophenylglycidyl ether as a reactant, instead of 1,2-epoxy-3-phenoxypropane, togive the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (m, 1H), 7.8 (m, 1H), 7.4-7.3 (m, 1H),7.1 (m, 1H), 6.9 (m, 1H), 6.3 (m, 1H), 4.4 (s, 2H), 4.1 (m, 1H), 4.0-3.9(m, 5H), 3.4 (m, 2H), 3.1 (m, 1H), 2.9 (m, 1H), 2.6 (m, 2H), 2.4 (m,1H), 2.2-2.05 (m, 1H), 1.9-1.6 (m, 3H), 1.5-1.3 (m, 2H)

EXAMPLE 804-amino-5-chloro-N-[[1-[3-(2-chlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 71 was followed using 2-chlorophenylglycidyl ether as a reactant, instead of 1,2-epoxy-3-phenoxypropane, togive the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (m, 1H), 7.8 (m, 1H), 7.4-7.2 (m, 2H),7.0-6.9 (m, 2H), 6.9-6.8 (m, 1H), 6.4 (s, 1H), 4.5-4.4 (m, 2H), 4.3-4.1(m, 3H), 3.9 (m, 3H), 3.4 (m, 2H), 3.1 (m, 1H0), 2.9 (m, 1H), 2.6 (m,2H), 2.4 (m, 1H), 2.1 (m, 1H) 1.9-1.6 (m, 3H), 1.5-1.3 (m, 2H)

EXAMPLE 814-amino-5-chloro-N-[[1-[3-(4-methylphenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 71 was followed using glycidyl4-methylphenyl ether as a reactant, instead of1,2-epoxy-3-phenoxypropane, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (m, 1H), 7.8 (m, 1H), 7.1 (m, 2H), 6.8(m, 2H), 6.4 (s, 1H), 4.4 (m, 2H), 4.1 (m, 1H), 4.0-3.9 (m, 5H), 3.4 (m,2H), 3.1 (m, 1H), 2.9 (m, 1H), 2.6 (m, 2H), 2.3 (m, 4H), 2.1 (m, 1H),1.9-1.6 (m, 3H), 1.4 (m, 2H)

EXAMPLE 824-amino-5-chloro-N-[[1-[3-(3,4-difluorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 71 was followed using 3,4-difluorophenylglycidyl ether as a reactant, instead of 1,2-epoxy-3-phenoxypropane, togive the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.2-7.0 (m, 1H),6.9-6.6 (m, 2H), 6.35 (s, 1H), 4.4 (s, 2H), 4.1 (m, 1H), 3.9 (m, 5H),3.4 (m, 2H), 3.1-2.9 (m, 2H), 2.6 (m, 2H), 2.4 (m, 1H), 2.1 (m, 1H),1.9-1.6 (m, 3H), 1.5-1.3 (m, 2H)

EXAMPLE 834-amino-5-chloro-N-[[1-[2-hydroxy-3-[4-(trifluoromethyl)phenoxy]propyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 71 was followed using glycidyl4-trifluoromethylphenyl ether as a reactant, instead of1,2-epoxy-3-phenoxypropane, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.75 (m, 1H), 7.6-7.5 (m, 2H),7.0 (m, 2H), 6.3 (s, 1H), 4.4 (s, 2H), 4.2-4.0 (m, 3H), 3.9 (s, 3H),3.35 (m, 2H), 3.1 (m, 1H), 2.9 (m, 1H), 2.5 (m, 2H), 2.35 (m, 1H), 2.1(m, 1H), 1.9-1.6 (m, 3H), 1.5-1.3 (m, 2H)

EXAMPLE 844-amino-5-chloro-N-[[1-[2-hydroxy-3-(4-phenylphenoxy)propyl]piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 71 was followed using glycidyl4-phenylphenyl ether as a reactant, instead of1,2-epoxy-3-phenoxypropane, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.75 (m, 1H), 7.5-6.9 (m, 9H),6.3 (s, 1H), 5.7 (m, 1H), 4.6 (m, 2H), 4.4 (s, 2H), 3.9 (s, 3H), 3.35(m, 2H), 2.9 (m, 2H), 2.4-2.3 (m, 2H), 2.0-1.8 (m, 2H), 1.8-1.5 (m, 3H),1.4-1.2 (m, 2H)

EXAMPLE 854-amino-5-chloro-N-[[1-(2-hydroxy-3-naphthalen-2-yloxypropyl)piperidin-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 71 was followed using2-(Naphthalen-2-yloxymethyl)-oxirane as a reactant, instead of1,2-epoxy-3-phenoxypropane, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.6-7.3 (m, 5H),7.0 (m, 2H), 6.3 (s, 1H), 4.4 (s, 2H), 4.3 (m, 1H), 4.1-4.0 (m, 2H), 3.9(s, 3H), 3.3 (m, 1H), 3.1 (m, 1H), 2.7 (m, 2H), 2.5 (m, 1H), 2.35 (m,1H), 1.9-1.6 (m, 3H), 1.6-1.4 (m, 2H)

EXAMPLE 864-amino-5-chloro-N-[[1-(2-hydroxy-3-phenylpropyl)piperidin-1-ium-4-yl]methyl]-2-methoxybenzamide;hydrochloride

The procedure given in Example 71 was followed using(2,3-epoxypropyl)benzene as a reactant, instead of1,2-epoxy-3-phenoxypropane, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.3 (m, 5H), 6.35(s, 1H), 4.45 (s, 2H), 4.0 (m, 1H), 3.95 (s, 3H), 3.35 (m, 2H), 3.05 (m,1H), 2.9 (m, 2H), 2.7 (m, 1H), 2.5-2.3 (m, 3H), 2.0 (m, 1H), 1.8-1.6 (m,3H), 1.4 (m, 2H)

EXAMPLE 87[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-phenoxypropan-2-yl]carbamate;hydrochloride

4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-methoxybenzamide(1 mmol) was dissolved in 10 mL of THF and added with 1,1′-carbonyldiimidazole (1.5 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 2 h, followed by the addition of excess ammoniumhydroxide (3 mL) at room temperature. After 2 h stirring at roomtemperature, water was added to terminate the reaction. The organiclayer was extracted 3 times with dichloromethane, dried, andconcentrated in vacuo. The resulting carbamate was dissolved in MC andthe solution treated with a solution of HCl in ether. The resultingprecipitate was filtered to give the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 8.0 (m, 1H), 7.66 (s,1H), 7.29 (m, 2H), 6.96 (m, 2H), 6.90 (m, 1H), 6.48 (s, 1H), 5.98 (s,2H), 5.35 (m, 1H), 4.15 (m, 2H), 3.83 (s, 3H), 3.3-2.1 (m, 6H), 3.0 (m,2H), 1.78 (m, 3H), 1.5 (m, 2H)

EXAMPLE 88[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-phenoxypropan-2-yl]piperidine-1-carboxylate;hydrochloride

The title compound was obtained by the method described in Example 87,except using piperidine (2 mmol) instead ammonium hydroxide.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.95 (m, 1H), 8.05 (m,1H), 7.66 (s, 1H), 7.31 (m, 2H), 6.96 (m, 3H), 6.48 (s, 1H), 6.0 (br,2H), 5.4 (m, 1H), 4.2 (m, 2H), 3.83 (s, 3H), 3.7-3.4 (m, 6H), 3.18 (m,4H), 3.0 (m, 2H), 1.77 (m, 3H), 1.7-1.3 (m, 8H)

EXAMPLE 89[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-(4-fluorophenoxy)propan-2-yl]3,5-dimethylpiperidine-1-carboxylate;hydrochloride

4-amino-5-chloro-N-[[1-[3-(4-fluorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide(1 mmol) was dissolved in 10 mL of THF and added with 1,1′-carbonyldiimidazole (1.5 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 2 h, followed by the addition of 3,5-dimethylpiperidine(2 mmol) at room temperature. After 2 h stirring at room temperature,water was added to terminate the reaction. The organic layer wasextracted 3 times with dichloromethane, dried, and concentrated invacuo. The resulting carbamate was dissolved in MC and the solutiontreated with a solution of HCl in ether. The resulting precipitate wasfiltered to give the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 8.0 (s, 1H), 7.66 (s,1H), 7.09 (m, 2H), 7.01 (m, 2H), 6.48 (s, 1H), 5.96 (s, 2H), 5.35 (br,1H), 4.17 (s, 2H), 4.0-3.8 (m, 7H), 3.46 (m, 2H), 3.18 (m, 4H), 3.0 (m,2H), 2.22 (m, 2H), 1.9-1.3 (m, 7H), 0.81 (m, 6H)

EXAMPLE 90[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-(4-chlorophenoxy)propan-2-yl]3,5-dimethylpiperidine-1-carboxylate;hydrochloride

The title compound was obtained by the method described in Example 89except that4-amino-5-chloro-N-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidewas used as a starting material instead of4-amino-5-chloro-N-[[1-[3-(4-fluorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 10.1 (br, 1H), 8.0 (m,1H), 7.66 (s, 1H), 7.34 (m, 2H), 7.00 (m, 2H), 6.48 (s, 1H), 5.96 (s,2H), 5.35 (m, 11H), 4.2 (m, 2H), 4.0-3.7 (m, 7H), 3.6-3.4 (m, 2H), 3.18(m, 4H), 3.0 (m, 2H), 2.2 (m, 2H), 1.9-1.2 (m, 7H), 0.9-0.6 (m, 6H)

EXAMPLE 91[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-(4-methoxyphenoxy)propan-2-yl]carbamate;hydrochloride

The procedure given in Example 87 was followed using4-amino-5-chloro-N-[[1-[3-(4-methoxyphenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 74 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.95 (m, 1H), 8.0 (m,1H), 7.66 (s, 1H), 6.88 (m, 6H), 6.48 (s, 1H), 5.35 (m, 1H), 4.07 (m,2H), 3.83 (s, 3H), 3.69 (s, 3H), 3.6 (m, 2H), 3.25 (m, 5H), 3.0 (m, 2H),2.0-1.5 (m, 5H)

EXAMPLE 92[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-(2,3-dichlorophenoxy)propan-2-yl]carbamate;hydrochloride

The procedure given in Example 87 was followed using4-amino-5-chloro-N-[[1-[3-(2,3-dichlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 75 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.3 (m, 1H), 7.1 (m,1H), 6.9 (m, 1H), 6.35 (s, 1H), 5.3 (m, 1H), 4.4 (m, 2H), 4.3 (m, 2H),3.95 (m, 3H), 3.8 (m, 2H), 3.4 (m, 2H), 3.1 (m, 1H), 2.9 (m, 1H),2.3-2.2 (m, 2H), 1.9-1.3 (m, 5H)

EXAMPLE 93[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-(2,3-dichlorophenoxy)propan-2-yl]pyrrolidine-1-carboxylate;hydrochloride

4-amino-5-chloro-N-[[1-[3-(2,3-dichlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide(1 mmol) was dissolved in 10 mL of THF and added with 1,1′-carbonyldiimidazole (1.5 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 2 h, followed by the addition of pyrrolidine (2 mmol) atroom temperature. After 2 h stirring at room temperature, water wasadded to terminate the reaction. The organic layer was extracted 3 timeswith dichloromethane, dried, and concentrated in vacuo. The resultingcarbamate was dissolved in MC and the solution treated with a solutionof HCl in ether. The resulting precipitate was filtered to give thetitle compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.9 (m, 1H), 7.2-7.1 (m, 2H),7.0-6.9 (m, 1H), 6.4 (s, 1H), 5.6 (m, 1H), 4.5-4.3 (m, 2H), 3.9 (m, 3H),3.6 (m, 1H), 3.55-3.3 (m, 5H), 2.8 (m, 2H), 2.55 (m, 3H), 2.1 (m, 1H),2.0-1.8 (m, 7H), 1.4-1.2 (m, 2H)

EXAMPLE 94[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-(2,3-dichlorophenoxy)propan-2-yl]piperidine-1-carboxylate;hydrochloride

The title compound was obtained by the method described in Example 93except using piperidine instead of pyrrolidine.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.3 (s, 1H), 7.2-7.1 (m, 2H), 7.0(m, 1H), 6.4 (s, 1H), 5.6 (m, 1H), 4.5 (m, 1H), 4.3 (m, 1H), 3.9 (m,3H), 33.6 (m, 1H), 3.5-3.3 (m, 5H), 2.9-2.7 (m, 2H), 2.5 (m, 4H),2.2-1.9 (m, 4H), 1.8-1.5 (m, 7H)

EXAMPLE 95[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-(2,3-dichlorophenoxy)propan-2-yl]azepane-1-carboxylate;hydrochloride

The title compound was obtained by the method described in Example 93except using hexamethyleneamine instead of pyrrolidine.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.9 (m, 1H), 7.3 (m, 1H), 7.2-7.1(m, 2H), 7.0-6.9 (m, 1H), 6.4 (s, 1H), 5.6 (m, 1H), 4.5 (m, 1H), 4.35(m, 1H), 4.2-4.0 (m, 2H), 3.95 (s, 3H), 3.7-3.3 (m, 6H), 2.8 (m, 2H),2.7-2.4 (m, 4H), 2.2-1.8 (m, 4H), 1.8-1.5 (m, 9H)

EXAMPLE 96[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-(2,4-dichlorophenoxy)propan-2-yl]carbamate;hydrochloride

The procedure given in Example 87 was followed using4-amino-5-chloro-N-[[1-[3-(2,4-dichlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 76 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (m, 1H), 7.9 (m, 1H), 7.4 (m, 1H), 7.1 (m,1H), 6.9 (m, 1H), 6.35 (m, 1H), 5.2 (m, 1H), 4.8 (m, 2H), 4.4 (m, 2H),4.2 (m, 2H), 3.9 (m, 3H), 3.4 (m, 2H), 3.0 (m, 2H), 2.75 (m, 2H), 2.2(m, 2H), 1.9-1.5 (m, 3H), 1.5-1.3 (m, 2H)

EXAMPLE 97[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-(2,5-dichlorophenoxy)propan-2-yl]carbamate;hydrochloride

The procedure given in Example 87 was followed using4-amino-5-chloro-N-[[1-[3-(2,5-dichlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 77 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (m, 1H), 7.8 (m, 1H), 7.3 (m, 1H), 7.0-6.9(m, 2H), 6.3 (m, 1H), 5.2 (m, 1H), 4.8 (m, 2H), 4.4 (m, 2H), 4.3-4.1 (m,2H), 3.9 (m, 3H), 3.3 (m, 2H), 3.0 (m, 2H), 2.7 (m, 2H), 2.2 (m, 2H),1.9-1.6 (m, 3H), 1.4-1.3 (m, 2H)

EXAMPLE 98[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-(2,6-dichlorophenoxy)propan-2-yl]carbamate;hydrochloride

The procedure given in Example 87 was followed using4-amino-5-chloro-N-[[1-[3-(2,6-dichlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 78 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (m, 1H), 7.9 (m, 1H), 7.4 (m, 1H), 7.05(m, 1H), 6.8 (m, 1H), 6.4 (m, 1H), 5.2 (m, 1H), 4.8 (s, 2H), 4.4 (s,2H), 4.2 (m, 2H), 3.9 (m, 3H), 3.4 (m, 2H), 3.0 (m, 2H), 2.8 (m, 2H),2.1 (m, 2H), 1.8-1.5 (m, 3H), 1.4-1.2 (m, 2H)

EXAMPLE 99[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-(3,4-dichlorophenoxy)propan-2-yl]carbamate;hydrochloride

The procedure given in Example 87 was followed using4-amino-5-chloro-N-[[1-[3-(3,4-dichlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 79 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.9 (m, 1H), 7.4-7.3 (m, 1H), 7.1(m, 1H), 6.9 (m, 1H), 6.35 (s, 1H), 5.2 (m, 1H), 4.8 (m 2H), 4.4 (m,2H), 4.2-4.0 (m, 2H), 3.95 (s, 3H), 3.35 (m, 2H), 3.1-2.9 (m, 2H), 2.6(m, 2H), 2.2-2.1 (m, 2H), 1.8-1.5 (m, 3H), 1.4-1.2 (m, 3H)

EXAMPLE 100[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-[4-(trifluoromethyl)phenoxy]propan-2-yl]carbamate;hydrochloride

The procedure given in Example 87 was followed using4-amino-5-chloro-N-[[1-[2-hydroxy-3-[4-(trifluoromethyl)phenoxy]propyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 83 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.75 (m, 1H), 7.7-7.5 (m, 2H),7.0 (m, 2H), 6.3 (s, 1H), 5.2 (m, 1H), 4.7 (m, 2H), 4.4 (s, 2H), 4.2 (m,2H), 3.9 (s, 3H), 3.35 (m, 2H), 2.9 (m, 2H), 2.7-2.6 (m, 2H), 2.2-2.05(m, 2H), 1.85 (m, 2H), 1.7 (m, 1H), 1.4-1.2 (m, 2H)

EXAMPLE 101[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-(4-phenylphenoxy)propan-2-yl]carbamate;hydrochloride

The procedure given in Example 87 was followed using4-amino-5-chloro-N-[[1-[2-hydroxy-3-(4-phenylphenoxy)propyl]piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 84 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) 8.15 (s, 1H), 7.8-7.7 (m, 5H), 7.5-7.1 (m, 5H),6.3 (s, 1H), 5.25 (m, 1H), 4.7 (m, 2H), 4.4-4.2 (m, 4H), 3.9 (s, 3H),3.35 (m, 2H), 3.1-2.9 (m, 2H), 2.7 (m, 2H), 2.2-2.1 (m, 2H), 1.8-1.5 (m,3H), 1.4-1.2 (m, 2H)

EXAMPLE 102[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-naphthalen-2-yloxypropan-2-yl]carbamate;hydrochloride

The procedure given in Example 87 was followed using4-amino-5-chloro-N-[[1-(2-hydroxy-3-naphthalen-2-yloxypropyl)piperidin-4-yl]methyl]-2-methoxybenzamidefrom Example 85 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.15 (s, 1H), 7.8 (m, 1H), 7.6-7.3 (m, 5H), 7.0(m, 2H), 6.3 (s, 1H), 5.25 (m, 1H), 4.9-4.7 (br, 2H), 4.4 (s, 2H), 4.2(m, 2H), 3.9 (s, 3H), 3.4-3.3 (m, 2H), 3.2-3.1 (m, 2H), 2.9-2.8 (m, 2H),2.4-2.15 (m, 2H), 1.9-1.6 (m, 3H), 1.6-1.4 (m, 2H)

EXAMPLE 103[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-phenylpropan-2-yl]carbamate;hydrochloride

The procedure given in Example 87 was followed using4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenylpropyl)piperidin-1-ium-4-yl]methyl]-2-methoxybenzamidefrom Example 86 as a reactant, instead of4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-methoxybenzamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.1 (s, 1H), 7.8 (m, 1H), 7.3-7.1 (m, 5H), 6.3(s, 1H), 5.1 (m, 1H), 4.95 (s, 2H), 4.6 (s, 2H), 4.0 (m, 1H), 3.85 (s,3H), 3.35 (m, 2H), 3.0-2.6 (m, 4H), 2.5-2.2 (m, 2H), 2.1-1.9 (m, 2H),1.8-1.5 (m, 3H), 1.3 (m, 2H)

EXAMPLE 104N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide;hydrochloride

A mixture of 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylicacid (piperidin-4-ylmethyl)-amide (3 mmol) and1,2-epoxy-3-phenoxypropane (3 mmol) was refluxed in 10 mL of isopropanolfor 3 h. This solution was concentrated on a rotary evaporator and themixture was purified by column chromatography. The resultingN-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamidewas dissolved in MC and the solution treated with a solution of HCl inether. The resulting precipitate was filtered to give the titlecompound.

1H NMR (DMSO, 200 MHz), ppm (δ): (free amine form) 8.83 (m, 1H), 8.05(m, 1H), 7.44 (m, 1H), 7.4-7.1 (m, 4H), 6.93 (m, 3H), 4.84 (m, 1H), 4.67(m, 1H), 3.88 (m, 2H), 3.22 (m, 2H), 2.92 (m, 2H), 2.4 (m, 2H), 1.99 (m,2H), 1.64 (m, 3H), 1.48 (m, 6H), 1.22 (m, 2H)

EXAMPLE 105N-[[1-[2-hydroxy-3-(4-nitrophenoxy)propyl]piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 104 was followed using glycidyl4-nitrophenyl ether as a reactant, instead of1,2-epoxy-3-phenoxypropane, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ9.0 (m, 1H), 8.35-8.2 (m, 3H), 7.2 (m, 3H), 7.0(m, 2H), 4.75 (m, 1H), 4.2-4.05 (m, 3H), 3.4 (t, 2H), 3.1 (m, 1H), 2.9(m, 1H), 2.55 (m, 2H), 2.4 (m, 1H), 2.05 (m, 1H), 1.85 (m, 2H), 1.7 (m,1H), 1.6 (d, 6H), 1.4 (m, 2H)

EXAMPLE 106N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 104 was followed using glycidyl4-methoxyphenyl ether as a reactant, instead of1,2-epoxy-3-phenoxypropane, to give the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (free amine form) 8.83 (m, 1H), 8.07(m, 1H), 7.44 (m, 1H), 7.15 (m, 2H), 6.85 (m, 4H), 4.78 (m, 1H), 4.66(m, 1H), 3.91-3.77 (m, 2H), 3.68 (s, 3H), 3.22 (m, 2H), 2.87 (m, 2H),2.36 (m, 2H), 1.96 (m, 2H), 1.60 (m, 2H), 1.48 (m, 7H), 1.23 (m, 2H)

EXAMPLE 107N-[[1-[3-(4-fluorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 104 was followed using 4-fluorophenylglycidyl ether as a reactant, instead of 1,2-epoxy-3-phenoxypropane, togive the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.65 (m, 1H), 8.88 (m,1H), 8.07 (m, 1H), 7.45 (m, 1H), 7.16 (m, 4H), 6.96 (m, 2H), 5.96 (m,1H), 4.67 (m, 1H), 4.34 (m, 1H), 3.94 (m, 2H), 3.56 (m, 2H), 3.26 (m,4H), 2.99 (m, 2H), 1.86 (m, 3H), 1.7-1.4 (m, 8H)

EXAMPLE 108N-[[1-[2-hydroxy-3-(2-methylphenoxy)propyl]piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 104 was followed using glycidyl2-methylphenyl ether as a reactant, instead of1,2-epoxy-3-phenoxypropane, to give the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.3 (m, 1H), 8.87 (m,1H), 8.07 (m, 1H), 7.45 (m, 1H), 7.18 (m, 5H), 6.90 (m, 2H), 5.94 (m,1H), 4.7 (m, 1H), 4.35 (m, 1H), 3.95 (m, 2H), 3.59 (m, 2H), 3.4-2.8 (m,6H), 2.18 (s, 3H), 1.87 (m, 3H), 1.7-1.4 (m, 8H)

EXAMPLE 109N-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 104 was followed using 4-chlorophenylglycidyl ether as a reactant, instead of 1,2-epoxy-3-phenoxypropane, togive the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.5 (m, 1H), 8.87 (m,1H), 8.07 (m, 1H), 7.5-6.9 (m, 6H), 5.97 (m, 1H), 4.67 (m, 1H), 4.35 (m,1H), 3.96 (m, 2H), 3.55 (m, 2H), 3.27 (m, 4H), 2.99 (m, 2H), 1.87 (m,3H), 1.7-1.4 (m, 8H)

EXAMPLE 110N-[[1-[3-(4-tert-butylphenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 104 was followed using 4-tert-butylphenylglycidyl ether as a reactant, instead of 1,2-epoxy-3-phenoxypropane, togive the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.32 (m, 1H), 8.87 (m,1H), 8.07 (m, 1H), 7.45 (m, 1H), 7.29 (m, 1H), 7.19 (m, 2H), 6.87 (m,2H), 5.95 (m, 1H), 4.65 (m, 1H), 4.29 (m, 1H), 3.93 (m, 2H), 3.54 (m,2H), 3.5-3.1 (m, 4H), 2.99 (m, 2H), 1.87 (m, 3H), 1.7-1.47 (m, 8H), 1.25(s, 9H)

EXAMPLE 111N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-3-methyl-2-oxobenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 104 was followed using3-methyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide as a reactant, instead of3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide, to give the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.3 (m, 1H), 8.83 (m,1H), 8.03 (m, 1H), 7.29-7.16 (m, 5H), 6.97 (m, 3H), 5.98 (m, 1H), 4.30(m, 1H), 3.96 (m, 2H), 3.61 (m, 2H), 3.5-3.1 (m, 5H), 2.93 (m, 2H), 2.6(m, 2H), 1.87 (m, 3H), 1.6 (m, 2H)

EXAMPLE 112N-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-3-methyl-2-oxobenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 104 was followed using3-methyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 4-chlorophenyl glycidyl ether as areactant, instead of3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 1,2-epoxy-3-phenoxypropane, to give thetitle compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.6 (m, 1H), 8.82 (m,1H), 8.02 (m, 1H), 7.4-6.9 (m, 7H), 5.98 (m, 1H), 4.35 (m, 1H), 3.95 (m,2H), 3.54 (m, 2H), 3.4-2.9 (m, 9H), 1.87 (m, 3H), 1.63 (m, 2H)

EXAMPLE 113N-[[1-[3-(4-tert-butylphenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-3-methyl-2-oxobenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 104 was followed using3-methyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 4-tert-butylphenyl glycidyl ether as areactant, instead of3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 1,2-epoxy-3-phenoxypropane, to give thetitle compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.64 (m, 1H), 8.82 (m,1H), 8.02 (m, 1H), 7.4-7.12 (m, 5H), 6.87 (m, 2H), 5.95 (m, 1H), 4.34(m, 1H), 3.93 (m, 2H), 3.58 (m, 2H), 3.5-3.1 (m, 7H), 3.0 (m, 2H), 1.87(m, 3H), 1.53 (m, 2H), 1.25 (s, 9H)

EXAMPLE 114N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidin-4-yl]methyl]-3-methyl-2-oxobenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 104 was followed using3-methyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and glycidyl 4-methoxyphenyl ether as areactant, instead of3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 1,2-epoxy-3-phenoxypropane, to give thetitle compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.45 (m, 1H), 8.82 (m,1H), 8.02 (m, 1H), 7.35-7.1 (m, 3H), 6.88 (m, 4H), 5.95 (m, 1H), 4.29(m, 1H), 3.89 (m, 2H), 3.69 (s, 3H), 3.6-3.1 (m, 7H), 2.99 (m, 4H), 1.87(m, 3H), 1.6 (m, 2H)

EXAMPLE 115N-[[1-[3-(4-fluorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-3-methyl-2-oxobenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 104 was followed using3-methyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 4-fluorophenyl glycidyl ether as areactant, instead of3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 1,2-epoxy-3-phenoxypropane, to give thetitle compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.5 (m, 1H), 8.82 (m,1H), 8.02 (m, 1H), 7.35-7.05 (m, 5H), 6.98 (m, 2H), 5.94 (m, 1H), 4.32(m, 1H), 3.94 (m, 2H), 3.55 (m, 2H), 3.5-3.1 (m, 7H), 2.98 (m, 2H), 1.87(m, 3H), 1.6 (m, 2H)

EXAMPLE 1163-ethyl-N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 104 was followed using3-ethyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide as a reactant, instead of3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.95 (m, 1H), 8.25 (m, 1H), 7.4-7.15 (m, 3H),7.1-6.9 (m, 5H), 4.1 (m, 2H), 4.0 (m, 2H), 3.55 (m, 1H), 3.4 (t, 2H),3.1 (m, 1H), 3.0 (m, 1H), 2.6 (m, 2H), 2.4 (m, 1H), 2.1 (m, 1H), 1.9-1.6(m, 3H), 1.5-1.3 (m, 5H)

EXAMPLE 1173-ethyl-N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 104 was followed using3-ethyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and glycidyl 4-methoxyphenyl ether as areactant, instead of3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 1,2-epoxy-3-phenoxypropane, to give thetitle compound.

1H-NMR (CDCl3, 200 MHz) δ 8.95 (m, 1H), 8.2 (m, 1H), 7.3-7.0 (m, 3H),6.8 (m, 4H), 4.25 (m, 1H), 4.0 (m, 4H), 3.8 (s, 3H), 3.5-3.3 (m, 4H),2.9 (m, 2H), 2.6 (m, 1H), 2.4 (m, 1H), 1.9 (m, 2H), 1.8-1.6 (m, 3H), 1.4(t, 3H)

EXAMPLE 1183-ethyl-N-[[1-[2-hydroxy-3-(2-methylphenoxy)propyl]piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 104 was followed using3-ethyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and glycidyl 2-methylphenyl ether as areactant, instead of3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 1,2-epoxy-3-phenoxypropane, to give thetitle compound.

1H-NMR (CDCl3, 200 MHz) δ 8.95 (m, 1H), 8.25 (m, 1H), 7.3-7.0 (m, 6H),6.85 (m, 2H), 4.3-3.9 (m, 5H), 3.4 (m, 2H), 3.2 (m, 1H), 3.05 (m, 1H),2.65 (m, 2H), 2.4 (m, 1H), 2.3 (s, 3H), 2.15 (m, 1H), 1.85 (m, 2H), 1.75(m, 1H), 1.6-1.3 (m, 5H)

EXAMPLE 119N-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-3-ethyl-2-oxobenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 104 was followed using3-ethyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 4-chlorophenyl glycidyl ether as areactant, instead of3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 1,2-epoxy-3-phenoxypropane, to give thetitle compound.

1H-NMR (CDCl3, 200 MHz) δ 8.95 (m, 1H), 8.25 (m, 1H), 7.2-7.0 (m, 4H),7.05 (m, 1H), 6.9 (m, 2H), 4.2 (m, 1H), 4.0 (m, 4H), 3.4 (m, 2H), 3.2(m, 1H), 3.05 (m, 1H), 2.65 (m, 2H), 2.4 (m, 1H), 2.0-1.7 (m, 3H),1.6-1.3 (m, 5H)

EXAMPLE 120[1-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]-3-phenoxypropan-2-yl]carbamate:hydrochloride

N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide(1 mmol) was dissolved in 10 mL of THF and added with 1,1′-carbonyldiimidazole (1.5 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 2 h, followed by the addition of excess ammoniumhydroxide (3 mL) at room temperature. After 2 h stirring at roomtemperature, water was added to terminate the reaction. The organiclayer was extracted 3 times with dichloromethane, dried, andconcentrated in vacuo. The resulting carbamate was dissolved in MC andthe solution treated with a solution of HCl in ether. The resultingprecipitate was filtered to give the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 10.2 (m, 1H), 8.88 (m,1H), 8.07 (m, 1H), 7.6-6.8 (m, 10H), 5.34 (m, 1H), 4.66 (m, 1H), 4.15(m, 2H), 3.55 (m, 2H), 3.26 (m, 4H), 3.04 (m, 2H), 1.85 (m, 3H), 1.59(m, 2H), 1.48 (m, 6H)

EXAMPLE 121[1-(4-methoxyphenoxy)-3-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]propan-2-yl]carbamate;hydrochloride

The procedure given in Example 120 was followed usingN-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamidefrom Example 106 as a reactant, instead ofN-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide,to give the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.7 (m, 1H), 8.80 (m,1H), 8.07 (m, 1H), 7.45 (m, 1H), 7.18 (m, 2H), 6.88 (m, 4H), 5.28 (m,1H), 4.65 (m, 1H), 4.07 (s, 2H), 3.69 (s, 3H), 3.58 (m, 2H), 3.5-3.2 (m,2H), 3.03 (m, 4H), 1.86 (m, 3H), 1.49 (m, 8H)

EXAMPLE 122[1-(4-fluorophenoxy)-3-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]propan-2-yl]carbamate;hydrochloride

The procedure given in Example 120 was followed usingN-[[1-[3-(4-fluorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamidefrom Example 107 as a reactant, instead ofN-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide,to give the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.5 (m, 1H), 8.88 (m,1H), 8.07 (m, 1H), 7.45 (m, 1H), 7.16 (m, 4H), 7.0-6.8 (m, 4H), 5.31 (m,1H), 4.66 (m, 1H), 4.11 (m, 2H), 3.60 (m, 2H), 3.5-3.2 (m, 4H), 3.00 (m,2H), 1.87 (m, 3H), 1.7-1.4 (m, 8H)

EXAMPLE 123[1-(2-methylphenoxy)-3-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]propan-2-yl]carbamate;hydrochloride

The procedure given in Example 120 was followed usingN-[[1-[2-hydroxy-3-(2-methylphenoxy)propyl]piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamidefrom Example 108 as a reactant, instead ofN-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide,to give the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.8 (m, 1H), 8.88 (m,1H), 8.04 (m, 1H), 7.45 (m, 1H), 7.18 (m, 5H), 6.90 (m, 4H), 5.35 (m,1H), 4.7 (m, 1H), 4.15 (m, 2H), 3.56 (m, 2H), 3.4-2.9 (m, 6H), 2.18 (s,3H), 1.86 (m, 3H), 1.7-1.4 (m, 8H)

EXAMPLE 124[1-(4-chlorophenoxy)-3-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]propan-2-yl]carbamate;hydrochloride

The procedure given in Example 120 was followed usingN-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamidefrom Example 109 as a reactant, instead ofN-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide,to give the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.35 (m, 1H), 8.88 (m,1H), 8.07 (m, 0.1H), 7.5-6.9 (m, 9H), 5.3 (m, 1H), 4.65 (m, 1H), 4.13(m, 2H), 3.60 (m, 2H), 3.0 (m, 4H), 2.84 (m, 2H), 1.87 (m, 3H), 1.7-1.1(m, 8H)

EXAMPLE 125[1-(4-tert-butylphenoxy)-3-[4-[[(3-methyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]propan-2-yl]carbamate;hydrochloride

The procedure given in Example 120 was followed usingN-[[1-[3-(4-tert-butylphenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamidefrom Example 110 as a reactant, instead ofN-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide,to give the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.64 (m, 1H), 8.82 (m,1H), 8.02 (m, 1H), 7.3-7.1 (m, 5H), 6.87 (m, 4H), 5.35 (m, 1H), 4.1 (m,2H), 3.58 (m, 2H), 3.5-3.1 (m, 7H), 3.0 (m, 2H), 1.87 (m, 3H), 1.53 (m,2H), 1.25 (s, 9H)

EXAMPLE 126[1-[4-[[(3-methyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]-3-phenoxypropan-2-yl]carbamate;hydrochloride

The procedure given in Example 120 was followed usingN-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-3-methyl-2-oxobenzimidazole-1-carboxamidefrom Example 111 as a reactant, instead ofN-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide,to give the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.3 (m, 1H), 8.83 (m,1H), 8.02 (m, 1H), 7.4-6.8 (m, 8H), 5.31 (m, 1H), 4.12 (m, 2H), 3.61 (m,2H), 3.5-2.81 (m, 7H), 2.4-2.1 (m, 2H), 1.81 (m, 3H), 1.52 (m, 2H)

EXAMPLE 127[1-(4-chlorophenoxy)-3-[4-[[(3-methyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]propan-2-yl]carbamate;hydrochloride

The procedure given in Example 120 was followed usingN-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-3-methyl-2-oxobenzimidazole-1-carboxamidefrom Example 112 as a reactant, instead ofN-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide,to give the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.5 (m, 1H), 8.83 (m,1H), 8.02 (m, 1H), 7.4-6.9 (m, 7H), 6.87 (m, 2H), 5.3 (m, 1H), 4.14 (m,2H), 3.6 (m, 2H), 3.4-3.1 (m, 5H), 3.0 (m, 4H), 1.87 (m, 3H), 1.63 (m,2H)

EXAMPLE 128[1-(4-tert-butylphenoxy)-3-[4-[[(3-methyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]propan-2-yl]carbamate;hydrochloride

The procedure given in Example 120 was followed usingN-[[1-[3-(4-tert-butylphenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-3-methyl-2-oxobenzimidazole-1-carboxamidefrom Example 113 as a reactant, instead ofN-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide,to give the title compound.

1H-NMR (DMSO-d6, 200 MHz, HCl form) δ9.64 (m, 1H), 8.82 (m, 1H), 8.02(m, 1H), 7.3-7.1 (m, 5H), 6.87 (m, 4H), 5.35 (m, 1H), 4.1 (m, 2H), 3.58(m, 2H), 3.5-3.1 (m, 7H), 3.0 (m, 2H), 1.87 (m, 3H), 1.53 (m, 2H), 1.25(s, 9H)

EXAMPLE 129[1-(4-methoxyphenoxy)-3-[4-[[(3-methyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]propan-2-yl]carbamate;hydrochloride

The procedure given in Example 120 was followed usingN-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidin-4-yl]methyl]-3-methyl-2-oxobenzimidazole-1-carboxamidefrom Example 114 as a reactant, instead ofN-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide,to give the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.65 (m, 1H), 8.82 (m,1H), 8.02 (m, 1H), 7.35-7.1 (m, 3H), 6.88 (m, 6H), 5.35 (m, 1H), 4.06(m, 2H), 3.69 (s, 3H), 3.6-3.1 (m, 7H), 3.04 (m, 4H), 1.87 (m, 3H), 1.6(m, 2H)

EXAMPLE 130[1-(4-fluorophenoxy)-3-[4-[[(3-methyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]propan-2-yl]carbamate;hydrochloride

The procedure given in Example 120 was followed usingN-[[1-[3-(4-fluorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-3-methyl-2-oxobenzimidazole-1-carboxamidefrom Example 115 as a reactant, instead ofN-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide,to give the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.45 (m, 1H), 8.83 (m,1H), 8.02 (m, 1H), 7.35-7.05 (m, 5H), 6.99 (m, 2H), 6.88 (m, 2H), 5.35(m, 1H), 4.11 (m, 2H), 3.60 (m, 2H), 3.5-3.1 (m, 7H), 3.04 (m, 2H), 1.87(m, 3H), 1.49 (m, 2H)

EXAMPLE 131[1-[4-[[(3-ethyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]-3-phenoxypropan-2-yl]carbamate;hydrochloride

The procedure given in Example 120 was followed using3-ethyl-N-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamidefrom Example 116 as a reactant, instead ofN-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.9 (m, 1H), 8.25 (m, 1H), 7.4-6.9 (m, 8H), 5.3(s, 2H), 5.2 (m, 1H), 4.15 (m, 2H), 4.0 (m, 2H), 3.35 (t, 2H), 3.0 (m,2H), 2.65 (m, 2H), 2.1 (m, 2H), 1.75 (m, 2H), 1.6 (m, 1H), 1.5-1.2 (m,5H)

EXAMPLE 132[1-[4-[[(3-ethyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]-3-(4-methoxyphenoxy)propan-2-yl]carbamate;hydrochloride

The procedure given in Example 120 was followed using3-ethyl-N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamidefrom Example 117 as a reactant, instead ofN-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.9 (m, 1H), 8.25 (m, 1H), 7.2 (m, 2H), 7.05(m, 1H), 6.85 (m, 4H), 5.15 (m, 1H), 5.0 (s, 2H), 4.15 (m, 2H), 4.0 (m,2H), 3.8 (s, 3H), 3.35 (t, 2H), 3.0 (m, 2H), 2.65 (m, 2H), 2.1 (m, 2H),1.75 (m, 2H), 1.6 (m, 1H), 1.5-1.2 (m, 5H)

EXAMPLE 133[1-[4-[[(3-ethyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]-3-(2-methylphenoxy)propan-2-yl]carbamate;hydrochloride

The procedure given in Example 120 was followed using3-ethyl-N-[[1-[2-hydroxy-3-(2-methylphenoxy)propyl]piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamidefrom Example 118 as a reactant, instead ofN-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.9 (m, 1H), 8.25 (m, 1H), 7.3-7.0 (m, 5H),6.85 (m, 2H), 5.25 (m, 1H), 5.05 (s, 2H), 4.15 (m, 2H), 4.0 (m, 2H),3.35 (t, 2H), 3.0 (m, 2H), 2.7 (d, 2H), 2.2 (s, 3H), 2.1 (m, 2H), 1.8(m, 2H), 1.6 (m, 1H), 1.5-1.2 (m, 5H)

EXAMPLE 134[1-(4-chlorophenoxy)-3-[4-[[(3-ethyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]propan-2-yl]carbamate;hydrochloride

The procedure given in Example 120 was followed usingN-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidin-4-yl]methyl]-3-ethyl-2-oxobenzimidazole-1-carboxamidefrom Example 119 as a reactant, instead ofN-[[1-(2-hydroxy-3-phenoxypropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ8.9 (m, 1H), 8.25 (m, 1H), 7.3-7.0 (m, 5H), 6.9(m, 2H), 5.2 (m, 1H), 5.0 (s, 2H), 4.15 (m, 2H), 4.0 (m, 2H), 3.35 (t,2H), 2.95 (m, 2H), 2.6 (d, 2H), 2.1 (m, 2H), 1.75 (m, 2H), 1.6 (m, 1H),1.5-1.2 (m, 5H)

EXAMPLE 1353-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide;hydrochloride

A mixture of 3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylicacid (piperidin-4-ylmethyl)-amide (5.0 mmol), 3-chloropropiophenone (6.0mmol), potassium carbonate (7.6 mmol) and potassium iodide (7.6 mmol)was refluxed in 15 mL of acetonitrile for 12 h. This solution was thenconcentrated on a rotary evaporator and diluted with ethyl acetate. Thismixture was then washed with brine, and the resulting organic layer wasdried and purified by column chromatography. This was dissolved inethanol (10 mL) and was added with sodium borohydride (10.0 mmol) at 0°C. and stirred at 25° C. for 2 h. This solution was concentrated on arotary evaporator and diluted with ethylacetate. This mixture was washedwith brine, dried, and concentrated in vacuo. The residue was purifiedby column chromatography. The resulting3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamidewas dissolved in MC and the solution treated with a solution of HCl inether. The resulting precipitate was filtered to give the titlecompound.

1H-NMR (CDCl3, 200 MHz) δ 8.95 (m, 1H), 8.35 (m, 1H), 7.5-7.1 (m, 9H),4.95 (m, 1H), 3.35-3.1 (m, 4H), 2.9 (m, 1H), 2.7 (m, 2H), 2.2 (m, 1H),2.1-1.6 (m, 5H), 1.5 (m, 2H), 1.3-1.0 (m, 5H)

EXAMPLE 136N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 135 was followed using3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide as a reactant, instead of3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 9.0 (m, 1H), 8.25 (m, 1H), 7.5-7.1 (m, 9H),4.95 (m, 1H), 4.75 (m, 1H), 3.35 (m, 2H), 3.15 (m, 2H), 2.8-2.55 (m,2H), 2.1 (m, 1H), 1.9 (m, 4H), 1.8-1.4 (m, 10H)

EXAMPLE 137N-[[1-[3-(4-fluorophenyl)-3-hydroxypropyl]piperidin-1-ium-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 135 was followed using3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 3-chloro-4′-fluoropropiophenone as areactant, instead of3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 3-chloropropiophenone, to give thetitle compound.

1H-NMR (CDCl3, 500 MHz) δ 9.00 (m, 1H), 8.28 (s, 1H), 7.36 (m, 2H), 7.20(m, 3H), 7.03 (m, 2H), 4.95 (m, 1H), 4.72 (m, 1H), 3.37 (m, 2H), 3.35(m, 1H), 3.22 (m, 1H), 2.81 (m, 1H), 2.71 (m, 1H), 2.28 (m, 1H), 2.11(m, 1H), 1.93 (m, 4H), 1.79 (m, 1H), 1.58 (m, 8H)

EXAMPLE 1383-cyclopropyl-N-[[1-[3-(4-fluorophenyl)-3-hydroxypropyl]piperidin-1-ium-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 135 was followed using3-chloro-4′-fluoropropiophenone as a reactant, instead of3-chloropropiophenone, to give the title compound.

1H-NMR (CDCl3, 500 MHz) δ 9.00 (m, 1H), 8.20 (s, 1H), 7.36 (m, 2H), 7.20(m, 3H), 7.05 (m, 2H), 4.96 (m, 1H), 3.37 (m, 3H), 3.30 (m, 1H), 2.92(m, 2H), 2.80 (m, 1H), 2.35 (m, 1H), 2.2 (m, 1H), 1.96 (m, 2H), 1.79 (m,2H), 1.65 (m, 3H), 1.20 (m, 2H), 1.05 (m, 2H)

EXAMPLE 139N-[[1-[3-(4-chlorophenyl)-3-hydroxypropyl]piperidin-1-ium-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 135 was followed using3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 3-chloro-4′-chloropropiophenone as areactant, instead of3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 3-chloropropiophenone, to give thetitle compound.

1H-NMR (CDCl3, 500 MHz) δ 9.00 (m, 1H), 8.27 (m, 1H), 7.33 (m, 4H), 7.18(m, 3H), 4.96 (m, 1H), 4.72 (m, 1H), 3.37 (m, 3H), 3.25 (m, 1H),2.87-2.70 (m, 2H), 2.40 (m, 1H), 2.13 (m, 1H), 1.95 (m, 5H), 1.78 (m,2H), 1.58 (m, 6H)

EXAMPLE 140N-[[1-[3-(4-chlorophenyl)-3-hydroxypropyl]piperidin-1-ium-4-yl]methyl]-3-cyclopropyl-2-oxobenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 135 was followed using3-chloro-4′-chloropropiophenone as a reactant, instead of3-chloropropiophenone, to give the title compound.

1H-NMR (CDCl3, 500 MHz) δ 8.94 (m, 1H), 8.20 (m, 1H), 7.33-7.19 (m, 7H),4.96 (m, 1H), 3.37 (m, 3H), 3.26 (m, 1H), 2.91 (m, 2H), 2.81 (m, 1H),2.32 (m, 1H), 2.15 (m, 1H), 1.95 (m, 4H), 1.77 (m, 2H), 1.62 (m, 3H),1.18 (m, 2H), 1.05 (m, 2H)

EXAMPLE 141N-[[1-[3-hydroxy-3-(4-methylphenyl)propyl]piperidin-1-ium-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 135 was followed using3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 3-chloro-4′-methylpropiophenone as areactant, instead of3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 3-chloropropiophenone, to give thetitle compound.

1H-NMR (CDCl3, 500 MHz) δ 9.01 (m, 1H), 8.26 (m, 1H), 7.37-7.15 (m, 7H),4.95 (m, 1H), 4.75 (m, 1H), 3.38 (m, 4H), 2.90 (m, 2H), 2.36 (s, 3H),2.10-1.65 (m, 9H), 1.60 (m, 6H)

EXAMPLE 1423-cyclopropyl-N-[[1-[3-hydroxy-3-(4-methylphenyl)propyl]piperidin-1-ium-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 135 was followed using3-chloro-4′-methylpropiophenone as a reactant, instead of3-chloropropiophenone, to give the title compound.

1H-NMR (CDCl3, 500 MHz) δ 8.95 (m, 1H), 8.20 (m, 1H), 7.42-7.13 (m, 7H),4.75 (m, 1H), 3.42-3.20 (m, 4H), 2.90 (m, 1H), 2.81 (m, 2H), 2.32 (m,3H), 2.18 (m, 1H), 1.95 (m, 3H), 1.80 (m, 2H), 1.65 (m, 3H), 1.20 (m,2H), 1.06 (m, 2H)

EXAMPLE 143N-[[1-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperidin-1-ium-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 135 was followed using3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 3-chloro-4′-methoxypropiophenone as areactant, instead of3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 3-chloropropiophenone, to give thetitle compound.

1H-NMR (CDCl3, 200 MHz) δ 9.05 (m, 1H), 8.25 (m, 1H), 7.35 (m, 3H), 7.2(m, 3H), 6.9 (m, 2H), 6.85 (m, 1H), 5.0 (m, 1H), 4.7 (m, 1H), 3.85 (s,3H), 3.7 (m, 1H), 3.5 (m, 1H), 3.4 (m, 2H), 3.25 (m, 2H), 3.0 (m, 3H),2.65 (m, 2H), 2.3 (m, 2H), 2.1 (m, 2H), 1.6 (m, 6H)

EXAMPLE 1443-cyclopropyl-N-[[1-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperidin-1-ium-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 135 was followed using3-chloro-4′-methoxypropiophenone as a reactant, instead of3-chloropropiophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.95 (m, 1H), 8.2 (m, 1H), 7.4-7.2 (m, 5H),6.9 (m, 2H), 4.9 (m, 1H), 3.8 (s, 3H), 3.35 (m, 2H), 3.2 (m, 2H), 2.9(m, 1H), 2.75 (m, 2H), 2.3-2.0 (m, 2H), 1.9 (m, 4H), 1.7 (m, 1H), 1.55(m, 2H), 1.2-1.0 (m, 4H)

EXAMPLE 145[3-[4-[[(3-cyclopropyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]-1-phenylpropyl]carbamate;hydrochloride

3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide(1 mmol) was dissolved in 10 mL of THF and added with 1,1′-carbonyldiimidazole (1.5 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 2 h, followed by the addition of excess ammoniumhydroxide (3 mL) at room temperature. After 2 h stirring at roomtemperature, water was added to terminate the reaction. The organiclayer was extracted 3 times with dichloromethane, dried, andconcentrated in vacuo. The resulting carbamate was dissolved in MC andthe solution treated with a solution of HCl in ether. The resultingprecipitate was filtered to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 9.00 (m, 1H), 8.20 (m, 1H), 7.31-7.18 (m, 8H),5.71 (m, 1H), 4.73 (br, 2H), 3.35 (m, 2H), 3.12 (br, 2H), 2.90 (m, 2H),2.80 (m, 1H), 2.30 (m, 2H), 2.07 (m, 2H), 1.86 (m, 2H), 1.75 (m, 1H),1.60 (m, 2H), 1.20 (m, 2H), 1.05 (m, 2H)

EXAMPLE 146[3-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-yl]-1-phenylpropyl]carbamate;hydrochloride

The procedure given in Example 145 was followed usingN-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamidefrom Example 136 as a reactant, instead of3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 9.0 (m, 1H), 8.3 (m, 1H), 7.8 (m, 1H), 7.4-7.1(m, 9H), 5.75 (m, 1H), 4.8-4.6 (m, 3H), 3.35 (m, 2H), 3.1 (m, 2H), 2.55(m, 3H), 2.4-2.0 (m, 5H), 1.9-1.6 (m, 4H), 1.5 (m, 6H)

EXAMPLE 147[1-(4-fluorophenyl)-3-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]propyl]carbamate;hydrochloride

The procedure given in Example 145 was followed usingN-[[1-[3-(4-fluorophenyl)-3-hydroxypropyl]piperidin-1-ium-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamidefrom Example 137 as a reactant, instead of3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide,to give the title compound.

1H-NMR (CDCl3, 500 MHz) δ 9.00 (m, 1H), 8.25 (s, 1H), 7.36 (m, 2H), 7.20(m, 3H), 7.05 (m, 2H), 5.69 (m, 1H), 4.72 (m, 1H), 3.36 (m, 2H), 3.20(m, 2H), 2.65 (m, 2H), 2.3 (m, 2H), 1.93 (m, 3H), 1.79 (m, 2H), 1.65 (m,2H), 1.58 (m, 6H)

EXAMPLE 148[3-[4-[[(3-cyclopropyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]-1-(4-fluorophenyl)propyl]carbamate;hydrochloride

The procedure given in Example 145 was followed using3-cyclopropyl-N-[[1-[3-(4-fluorophenyl)-3-hydroxypropyl]piperidin-1-ium-4-yl]methyl]-2-oxobenzimidazole-1-carboxamidefrom Example 138 as a reactant, instead of3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.89 (m, 1H), 8.20 (m, 1H), 7.35-7.19 (m, 5H),7.03 (m, 2H), 5.68 (m, 1H), 4.78 (br, 2H), 3.33 (m, 2H), 3.03 (m, 2H),2.90 (m, 1H), 2.47 (m, 2H), 2.20 (m, 1H), 2.06 (m, 3H), 1.81 (m, 2H),1.65 (m, 1H), 1.45 (m, 2H), 1.17 (m, 2H), 1.05 (m, 2H)

EXAMPLE 149[1-(4-chlorophenyl)-3-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]propyl]carbamate;hydrochloride

The procedure given in Example 145 was followed usingN-[[1-[3-(4-chlorophenyl)-3-hydroxypropyl]piperidin-1-ium-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamidefrom Example 139 as a reactant, instead of3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.98 (m, 1H), 8.26 (m, 1H), 7.34-7.17 (m, 7H),5.67 (m, 1H), 4.72 (m, 3H), 3.35 (m, 2H), 3.06 (m, 2H), 2.50 (m, 2H),2.25 (m, 1H), 2.12 (m, 1H), 2.05 (m, 2H), 1.85 (m, 2H), 1.80 (m, 1H),1.58 (m, 6H), 1.28 (m, 2H)

EXAMPLE 150[1-(4-chlorophenyl)-3-[4-[[(3-cyclopropyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]propyl]carbamate;hydrochloride

The procedure given in Example 145 was followed usingN-[[1-[3-(4-chlorophenyl)-3-hydroxypropyl]piperidin-1-ium-4-yl]methyl]-3-cyclopropyl-2-oxobenzimidazole-1-carboxamidefrom Example 140 as a reactant, instead of3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide,to give the title compound.

1H-NMR (CDCl3, 500 MHz) δ 8.93 (m, 1H), 8.19 (m, 1H), 7.35-7.20 (m, 7H),5.68 (m, 1H), 4.78 (m, 2H), 3.36 (m, 2H), 3.18 (m, 2H), 2.91 (m, 2H),2.65 (m, 2H), 2.31 (m, 2H), 2.15 (m, 2H), 1.89 (m, 2H), 1.75 (m, 2H),1.63 (m, 3H), 1.19 (m, 2H), 1.06 (m, 2H)

EXAMPLE 151[1-(4-methylphenyl)-3-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]propyl]carbamate;hydrochloride

The procedure given in Example 145 was followed usingN-[[1-[3-hydroxy-3-(4-methylphenyl)propyl]piperidin-1-ium-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamidefrom Example 141 as a reactant, instead of3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.97 (m, 1H), 8.25 (m, 1H), 7.30-7.13 (m, 7H),5.67 (m, 1H), 4.73 (m, 3H), 3.50 (m, 1H), 3.32 (m, 2H), 3.10 (m, 2H),2.58 (m, 2H), 2.37 (m, 3H), 2.28 (m, 1H), 2.11 (m, 3H), 1.85 (m, 3H),1.72 (m, 1H), 1.58 (m, 6H)

EXAMPLE 152[3-[4-[[(3-cyclopropyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]-1-(4-methylphenyl)propyl]carbamate;hydrochloride

The procedure given in Example 145 was followed using3-cyclopropyl-N-[[1-[3-hydroxy-3-(4-methylphenyl)propyl]piperidin-1-ium-4-yl]methyl]-2-oxobenzimidazole-1-carboxamidefrom Example 142 as a reactant, instead of3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.90 (m, 1H), 8.20 (s, 1H), 7.32-7.13 (m, 7H),5.66 (m, 1H), 4.73 (br, 2H), 3.35 (m, 2H), 3.12 (m, 2H), 2.91 (m, 1H),2.60 (m, 2H), 2.40 (s, 3H), 2.27 (m, 2H), 1.61 (m, 2H), 1.87 (m, 2H),1.72 (m, 1H), 1.59 (m, 2H), 1.20 (m, 2H), 1.06 (m, 2H)

EXAMPLE 153[1-(4-methoxyphenyl)-3-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]propyl]carbamate;hydrochloride

The procedure given in Example 145 was followed usingN-[[1-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperidin-1-ium-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamidefrom Example 143 as a reactant, instead of3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 9.0 (m, 1H), 8.25 (m, 1H), 7.35 (m, 3H), 7.2(m, 3H), 6.9 (m, 2H), 5.65 (m, 1H), 4.95 (m, 2H), 4.7 (m, 1H), 3.8 (s,3H), 3.4 (m, 2H), 3.2 (m, 2H), 2.7 (m, 2H), 2.4-2.1 (m, 4H), 1.9 (m,3H), 1.7 (m, 2H), 1.6 (m, 6H)

EXAMPLE 154[3-[4-[[(3-cyclopropyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]-1-(4-methoxyphenyl)propyl]carbamate;hydrochloride

The procedure given in Example 145 was followed using3-cyclopropyl-N-[[1-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperidin-1-ium-4-yl]methyl]-2-oxobenzimidazole-1-carboxamidefrom Example 144 as a reactant, instead of3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) 8.95 (m, 1H), 8.2 (m, 1H), 7.4-7.2 (m, 5H), 6.95(m, 2H), 5.65 (m, 1H), 4.8 (m, 2H), 3.8 (s, 3H), 3.4 (m, 2H), 3.2 (m,2H), 2.9 (m, 1H), 2.7 (m, 2H), 2.5-2.1 (m, 4H), 1.9 (m, 3H), 1.75 (m,2H), 1.4-1.0 (m, 4H)

EXAMPLE 155N-[[1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide;hydrochloride

A mixture of 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylicacid (piperidin-4-ylmethyl)-amide (5.0 mmol),2-bromo-4′-fluoroacetophenone (6.0 mmol) and potassium carbonate (7.6mmol) was stirred in 15 mL of acetonitrile for 2 h. This solution wasthen concentrated on a rotary evaporator and diluted with ethyl acetate.This mixture was then washed with brine, and the resulting organic layerwas dried and purified by column chromatography. This was dissolved inethanol (10 mL) and was added with sodium borohydride (10.0 mmol) at 0°C. and stirred at 25° C. for 2 h. This solution was concentrated on arotary evaporator and diluted with ethylacetate. This mixture was washedwith brine, dried, and concentrated in vacuo. The residue was purifiedby column chromatography. The resultingN-[[1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-1-ium-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamidewas dissolved in MC and the solution treated with a solution of HCl inether. The resulting precipitate was filtered to give the titlecompound.

1H-NMR (CDCl3, 500 MHz) S 9.01 (m, 1H), 8.26 (m, 1H), 7.37 (m, 2H), 7.20(m, 3H), 7.05 (m, 2H), 4.90 (br, 2H), 3.38 (m, 2H), 3.30 (m, 1H), 3.08(m, 1H), 2.63 (m, 2H), 2.50 (m, 1H), 2.25 (m, 1H), 1.91 (m, 2H), 1.80(m, 1H), 1.59 (m, 8H)

EXAMPLE 156N-[[1-[2-hydroxy-2-(3-methoxyphenyl)ethyl]piperidin-1-ium-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 155 was followed using2-bromo-3′-methoxyacetophenone as a reactant, instead of2-bromo-4′-fluoroacetophenone, to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 9.05 (m, 1H), 8.3 (m, 1H), 7.35-7.1 (m, 5H),7.0 (m, 2H), 6.85 (m, 1H), 4.9 (m, 1H), 4.85 (m, 1H), 3.95 (s, 3H), 3.4(m, 3H), 3.1 (m, 1H), 2.85 (m, 2H), 2.5 (m, 1H), 2.3 (m, 1H), 1.95-1.8(m, 3H), 1.6-1.5 (m, 8H)

EXAMPLE 1573-cyclopropyl-N-[[1-[2-hydroxy-2-(3-methoxyphenyl)ethyl]piperidin-1-ium-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide;hydrochloride

The procedure given in Example 155 was followed using3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 2-bromo-3′-methoxyacetophenone as areactant, instead of3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid(piperidin-4-ylmethyl)-amide and 2-bromo-4′-fluoroacetophenone, to givethe title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.95 (m, 1H), 8.25 (m, 1H), 7.35-7.2 (m, 4H),7.0 (m, 2H), 6.85 (m, 1H), 4.85 (m, 1H), 3.95 (s, 3H), 3.35 (m, 3H),2.95 (m, 2H), 2.6 (m, 2H), 2.45 (m, 1H), 2.2 (m, 1H), 1.9 (m, 2H), 1.85(m, 1H), 1.5 (m, 2H), 1.3-1.0 (m, 4H)

EXAMPLE 158[1-(4-fluorophenyl)-2-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]ethyl]carbamate;hydrochloride

The procedure given in Example 145 was followed usingN-[[1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamidefrom Example 155 as a reactant, instead of3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide,to give the title compound.

1H-NMR (CDCl3, 500 MHz) δ 8.97 (m, 1H), 8.26 (m, 1H), 7.37 (m, 2H), 7.18(m, 3H), 7.05 (m, 2H), 5.82 (m, 1H), 5.00 (m, 1H), 4.72 (m, 1H), 3.35(m, 2H), 3.15-2.95 (m, 2H), 2.71 (m, 1H), 2.62 (m, 1H), 2.26 (m, 2H),1.95 (m, 1H), 1.85 (m, 2H), 1.70 (m, 2H), 1.58 (m, 6H)

EXAMPLE 159[1-(3-methoxyphenyl)-2-[4-[[(2-oxo-3-propan-2-ylbenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]ethyl]carbamate;hydrochloride

The procedure given in Example 145 was followed usingN-[[1-[2-hydroxy-2-(3-methoxyphenyl)ethyl]piperidin-1-ium-4-yl]methyl]-2-oxo-3-propan-2-ylbenzimidazole-1-carboxamidefrom Example 156 as a reactant, instead of3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 9.05 (m, 1H), 8.25 (m, 1H), 7.35-7.1 (m, 4H),7.0-6.85 (m, 3H), 5.9 (m, 1H), 4.7 (m, 1H), 3.8 (s, 3H), 3.5-3.1 (m,4H), 2.8 (m, 1H), 2.5 (m, 2H), 2.1-1.85 (m, 6H), 1.6 (m, 6H)

EXAMPLE 160[[2-[4-[[(3-cyclopropyl-2-oxobenzimidazole-1-carbonyl)amino]methyl]piperidin-1-ium-1-yl]-1-(3-methoxyphenyl)ethyl]carbamate;hydrochloride

The procedure given in Example 145 was followed using3-cyclopropyl-N-[[1-[2-hydroxy-2-(3-methoxyphenyl)ethyl]piperidin-1-ium-4-yl]methyl]-2-oxobenzimidazole-1-carboxamidefrom Example 157 as a reactant, instead of3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidin-4-yl]methyl]-2-oxobenzimidazole-1-carboxamide,to give the title compound.

1H-NMR (CDCl3, 200 MHz) δ 9.0 (m, 1H), 8.2 (m, 1H), 7.4-7.2 (m, 4H),7.05-6.9 (m, 3H), 5.95 (m, 1H), 3.85 (s, 3H), 3.6-3.4 (m, 3H), 2.95 (m,2H), 2.7 (m, 2H), 2.2-1.8 (m, 5H), 1.7 (m, 2H), 1.4-1.0 (m, 4H)

EXAMPLE 161 Gastric Emptying Enhancing Activity

ICR CD strain male mice (body weight, 25˜30 g; 8 mice per one group)were fasted for 24 h but allowed free access to water until 3 hoursbefore the test.

Compounds to be tested for promoting GI motility were injectedintraperitoneally or given orally at 30 min or 60 min prior to phenolred meal administration. Fifteen (15) min after administration of a testmeal (0.5% Phenol red in 1.5% methylcellulose solution), mice weresacrificed and the stomach (pylorus˜cardia) was removed and collected tovial. The stomach was homogenized with its contents in 0.1N NaOH and themixture was centrifuged (700*g) for 20 min. 2.5 mL of the supernatantwas added to 0.25 mL of trichloroacetic acid solution (20% w/v) toprecipitate proteins. After centrifuging (2600*g) for 20 min, 0.5 mL ofthe supernatant was added to 0.25 mL of 1N NaOH. The mixture washomogenized and its absorbance (Abs) was read at 560 nm.

In each experiment, one group was sacrificed just after theadministration of the test meal and was considered as a standard (0%emptying). The gastric emptying (GE) at the 15 min period was calculatedaccording to the following formula.GE (%)=(1−Abs_(test)/Abs_(standard))×100Increase (%)=(GE %_(test)−GE %_(vehicle))/GE %_(vehicle)*100

As shown in Table 1, most compounds of this invention exhibited a potentgastric emptying enhancing effect at a dose of 3 mg/kg.

As is clear from the above experimental result, the compounds of thestructural formula (I) and pharmaceutically useful salts have excellentgastrointestinal motility enhancing activity, and hence are useful fortreating the diseases of the gastrointestinal tract such as irritablebowel syndrome (IBS), specifically constipation-predominant IBS, andgastric motility disorder.

5-Hydroxytryptamine (5-HT) released from enterochromaffin cells regulategastrointestinal function in either an excitatory or inhibitory manner.The gastrointestinal motility enhancing activity is characteristic ofagonism on 5-HT4 receptors. 5-HT4 receptor agonists can stimulate upperor lower gut motility while 5-HT4 antagonists inhibit the enhanced gutmotility by 5-HT4 agonists.

The compounds of the structural formula (I) have 5-HT4 receptor bindingactivity and stimulate gut motility (see Table 1). Therefore, enhancinggut motility of the compounds of the structural formula (I) is believedto be mediated by agonism on 5-HT4 receptors.

TABLE 1 Gastric Emptying Enhancing Activity (3.0 mg/kg i.p.) ExampleIncrease % 2 42.6% 3 71.1% 4 74.1% 5 76.1% 8 51.6% 9 55.8% 13 14.0% 1578.7% 16 53.6% 17 22.1% 23 55.8% 24 71.1% 27 48.5% 29 61.3% 31 79.3% 3240.0% 33 115.2% 35 105.5% 36 55.2% 37 70.7% 38 49.1% 39 40.0% 40 51.6%41 24.3% 42 42.7% 43 46.1% 45 51.4% 46 45.9% 47 25.9% 48 3.5% 49 17.8%50 3.9% 51 122.1% 52 131.0% 53 28.4% 54 89.2% 55 66.7% 56 134.7% 5729.0% 58 48.3% 59 48.0% 60 14.2% 61 44.3% 62 17.9% 63 24.4% 64 7.3% 6593.1% 66 84.1% 68 52.9 70 67.5% 71 63.7% 72 48.1% 74 46.7% 83 42.5% 8844.1% 89 45.3% 96 105.0% 97 71.4% 98 63.6% 99 47.5% 100 46.1% 103 88.8%104 81.0% 111 37.2% 121 46.8% 122 6.8% 123 56.8% 124 45.6% 126 93.3% 12711.3% 129 5.4% 135 90.3% 136 64.1% 146 83.0%

Hypersensitivity to colorectal distension is common in patients with IBSand may be responsible for the major symptom of visceral pain. Bothinflammatory and non-inflammatory animal models of visceral hyperalgesiato distension as will be described in Example 162 and 163, respectively,have been developed to investigate the effect of a compound on visceralpain in IBS.

EXAMPLE 162 TNBS-Induced Colorectal Hypersensitivity Test

Wistar rats (body weight, 200-225 g; 8-10 rats per a group) weresurgically prepared for electromyographic recording to a previouslydescribed technique (Morteau et al., Dig Dis Sci, 1994,39(6):1239-1248). After laparotomy, three groups of three electrodeswere implanted in the striated muscles of the abdomen.

Electrodes were exteriorized on the back of the neck and protected by aglass tube attached to the skin.

Colorectal distension (CRD) was performed with balloon inflated by 5 minsteps of 15 mmHg from 0 to 60 mmHg by connecting the balloon tocomputerized barostat. Rats were submitted to CRD 1 day before (basalcondition) and 3 days after intra-rectal administration oftrinitrobenzene sulfonic acid (TNBS 80 mg/kg intrarectally). Colonicpressure and balloon volume were continuously monitored on apotentiometric recorder (L6514, Linseis, Selb, Germany) with a paperspeed of 1 cm·min−1.

Five day after the administration of TNBS, rats were treated with testarticle or their vehicle (carboxymethyl cellulose 0.5%, 1 mL po) onehour before distension. The number of spike bursts that correspond toabdominal contractions was determined per 5 min periods. Values areexpressed as means±SEM. Statistical analysis was performed using theStudent's “t” test and criterion for statistical significance wasp<0.05.

Table 2 summarizes the result of the activity of the compound obtainedin Example 68 as a test compound in the TNBS-induced colorectalhypersensitivity model. Significant decreases in abdominal contractionare observed at 10 mg/kg and 30 mg/kg of test compound. This resultshows that the compound according to one embodiment of the presentinvention has visceral pain reducing activity in rat preclinical model.

TABLE 2 Effect of a test compound on TNBS-induced colorectalhypersensitivity in rats Number of abdominal contraction/5 min 0 mmHg^(a)) 15 mmHg ^(a)) 30 mmHg ^(a)) 45 mmHg ^(a)) 60 mmHg ^(a)) Vehicle1.1 ± 0.6  5.3 ± 1.6  14.0 ± 2.9 25.7 ± 2.9 30.7 ± 2.7 TNBS + Vehicle3.2 ± 1.1 13.3 ± 1.6  27.5 ± 4.0 39.0 ± 5.2 45.5 ± 4.7 TNBS + 4.7 ± 1.214.7 ± 2.5 19.9* ± 2.5 31.0 ± 3.9 37.1 ± 6.0 test compound (10 mg/kg,po) TNBS + 2.1 ± 0.7 7.3* ± 1.8 15.3* ± 3.0 21.4* ± 2.1  28.3* ± 3.1 test compound (30 mg/kg, po) ^(a)) Pressure of distension *p < 0.05significantly different from “TNBS + Vehicle”

EXAMPLE 163 PRS (Partial Restraint Stress)-Induced ColorectalHypersensitivity Test

Adult female Wistar rats (body weight, 225-250 g; 6-7 rats per group)were prepared for electromyography. After anaesthetization, three pairsof nichrome wire electrodes were implanted bilaterally in the striatedmuscles at 3 cm laterally from the midline. The free ends of electrodeswere exteriorized on the back of the neck and protected by a glass tubeattached to the skin.

PRS; a relatively mild stress, was performed as previously described inBradesi S, Eutamene H, Garcia-Villar R, Fioramonti J, Bueno L; ‘Acuteand chronic stress differently affect visceral sensitivity to rectaldistension in female rats.’ Neurogastroenterol. Mot. (2002) 14, 75-82.

Rats were placed in a plastic tunnel, where they are not allowed to moveor escape several days before colorectal distension (CRD). The balloon,connected to a barostat was inflated progressively by steps of 15 mmHg,from 0, 15, 30, 45 and 60 mmHg, each step of inflation lasting 5 min. Todetermine the antinoiciceptive effect of a test compound on PRS-inducedvisceral hypersensitivity, the test compound or vehicle (CMC0.5%) wasgiven orally (PO), lhr 15 min after the beginning of the PRS. Threehours before and 15 min after the stress session, a CRD was performed.

The number of spike bursts corresponding to abdominal contractions per 5min periods was determined for each volume of distension. Colonicpressure and balloon volume were continuously monitored on apotentiometric recorder (L6514, Linseis, Selb, Germany). Values areexpressed as means±SEM.

Statistical analysis was performed by a one way analysis of variance(ANOVA) followed by a Dunnett test. p<0.05 was considered assignificant.

Table 3 summarizes the results of the activity of the compound obtainedin Example 68 as a test compound in the PRS-induced colorectalhypersensitivity model. Significant decreases in abdominal contractionare observed at 30 mg/kg. This result shows that the compound accordingto one embodiment of the present invention has visceral pain reducingactivity.

TABLE 3 Effect of a test compound on PRS-induced colorectalhypersensitivity in rats Number of abdominal contraction/5 min 0 mmHg^(a)) 15 mmHg ^(a)) 30 mmHg ^(a)) 45 mmHg ^(a)) 60 mmHg ^(a)) Vehicle0.7 ± 0.3 3.7 ± 1.4 13.3 ± 2.2 18.8 ± 4.1 23.3 ± 3.9 PRS + vehicle 2.0 ±0.8 7.0 ± 3.1 33.2 ± 7.9 54.2 ± 6.5 57.8 ± 6.3 PRS + 4.9 ± 1.1 2.7 ± 0.911.9* ± 2.3  35.3* ± 5.3  46.0 ± 3.3 Test compound (30 mg/kg, po) ^(a))Pressure of distension *p < 0.05 compared to “PRS + vehicle”

What is claimed is:
 1. A method of preparing a piperidine compound ofstructural formula (I), comprising: a step of reacting the compoundrepresented by structural formula (VI) with 1,1′-carbonyldiimidazole(CDI) and then reacting with an amine compound represented by structuralformula (VIII):

wherein m is an integer of 1 or 2; n is an integer from 0 to 2; A isselected from a phenyl group and a benzimidazole group, wherein thephenyl group is substituted with one or more groups independentlyselected from hydrogen, a C₁-C₆ linear or branched alkyl group, a C₁-C₆linear or branched alkoxy group, an amino group, and a halogen, and thebenzimidazole group is substituted with one or more groups independentlyselected from hydrogen, a C₁-C₆ linear or branched alkyl group, a C₁-C₆linear or branched alkoxy group, a C₃-C₇ cyclic alkyl group, an aminogroup, a halogen, and an oxo group; X is OCONR₁R₁R₂ wherein R₁ and R₂are independently selected from hydrogen, a C₁-C₆ linear or branchedalkyl group, a benzyl group, and a 5- to 7-membered cyclic orheterocyclic compound that is substituted with one or more groupsindependently selected from a C₁ to C₆ alkyl, and R₁ and R₂ form a 5- to7-membered heterocyclic ring together with a nitrogen atom to which theyare attached; B is selected from a phenyl group, a phenoxy group, athienyl group, and a naphthyl group, wherein the phenyl group, phenoxygroup, thienyl group, or naphthyl group is substituted with one or moregroups independently selected from hydrogen, halogen, nitro, cyano,methanesulfonyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy,phenyl, a C₁-C₆ linear or branched alkyl group, and a C₁-C₆ linear orbranched alkoxy group.
 2. The method of claim 1, wherein the methodfurther comprises a step of preparing pharmaceutically acceptable saltsof the piperidine compound of structural formula (I), by reacting thepiperidine compound with HX that represents an acid being capable offorming a pharmaceutically useful salt with the basic nitrogen atom. 3.The method of claim 2, wherein the acid is hydrochloric acid, sulfuricacid, phosphoric acid, acetic acid, benzoic acid, citric acid, malonicacid, salicylic acid, malic acid, fumaric acid, oxalic acid, succinicacid, tartaric acid, lactic acid, gluconic acid, ascorbic acid, maleicacid, aspartic acid, benzene sulfonic acid, methane sulfonic acid,ethane sulfonic acid, hydroxymethane sulfonic acid or hydroxyethanesulfonic acid.
 4. The method of claim 1, wherein the reaction isperformed using 0.005 to 0.1 moles of the compound represented bystructural formula (VI), 2.0 to 3.0 equivalents of1,1′-carbonyldiimidazole (CDI) and 1 to 1000 equivalents of an aminecompound represented by the general structural formula (VIII) at atemperature of 10 to 30° C.
 5. The method of claim 1, wherein apiperidine compound of structural formula (I) and pharmaceuticallyacceptable salts thereof is prepared by the method comprising, preparinga piperidine compound of structural formula (VI) and pharmaceuticallyacceptable salts thereof, by reacting the compound represented bystructural formula (XXXIII) with an alkyl halide represented by thestructural formula (XII-2), or an epoxide represented by the structuralformula (XIII);

reacting the piperidine compound represented by structural formula (VI)with 1,1′-carbonyldiimidazole (CDI); and reacting with an amine compoundrepresented by structural formula (VIII):

wherein, m is an integer of 1 or 2; n is an integer from 0 to 2; A isselected from a phenyl group and a benzimidazole group, wherein thephenyl group is substituted with one or more groups independentlyselected from hydrogen, a C₁-C₆ linear or branched alkyl group, a C₁-C₆linear or branched alkoxy group, an amino group, and a halogen, and thebenzimidazole group is substituted with one or more groups independentlyselected from hydrogen, a C₁-C₆ linear or branched alkyl group, a C₁-C₆linear or branched alkoxy group, a C₃-C₇ cyclic alkyl group, an aminogroup, a halogen, and an oxo group; B is selected from a phenyl group, aphenoxy group, a thienyl group, and a naphthyl group, wherein the phenylgroup, phenoxy group, thienyl group, or naphthyl group is substitutedwith one or more groups independently selected from hydrogen, halogen,nitro, cyano, methanesulfonyl, trifluoromethyl, trifluoromethoxy,difluoromethoxy, phenyl, a C₁-C₆ linear or branched alkyl group, and aC₁-C₆ linear or branched alkoxy group, and Z is a halogen.
 6. The methodof claim 1, wherein the piperidine compound of structural formula (I) isselected from the group consisting of the following compounds andpharmaceutically acceptable salts thereof:[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(3-methoxyphenyl)ethyl] carbamate,[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-fluorophenyl)propyl]carbamate, (S)-3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-fluorophenyl)propylcarbamate,(R)-[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-1-(4-fluorophenyl)propyl]carbamate, and[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-3-phenylpropan-2-yl]carbamate.
 7. The method of claim 1, wherein a piperidine compound ofstructural formula (I) and pharmaceutically acceptable salts thereof isprepared by the method comprising, preparing a piperidine compound ofstructural formula (VI) and pharmaceutically acceptable salts thereof,by reacting the compound represented by structural formula (XXXIII) withan alkyl halide represented by the structural formula (XII-1) andNaBH_(4;)

reacting the piperidine compound represented by structural formula (VI)with 1,1′-carbonyldiimidazole (CDI); and reacting with an amine compoundrepresented by structural formula (VIII):

wherein, m is an integer of 1 or 2; n is an integer from 0 to 2; A isselected from a phenyl group and a benzimidazole group, wherein thephenyl group is substituted with one or more groups independentlyselected from hydrogen, a C₁-C₆ linear or branched alkyl group, a C₁-C₆linear or branched alkoxy group, an amino group, and a halogen, and thebenzimidazole group is substituted with one or more groups independentlyselected from hydrogen, a C₁-C₆ linear or branched alkyl group, a C₁-C₆linear or branched alkoxy group, a C₃-C₇ cyclic alkyl group, an aminogroup, a halogen, and an oxo group; B is selected from a phenyl group, aphenoxy group, a thienyl group, and a naphthyl group, wherein the phenylgroup, phenoxy group, thienyl group, or naphthyl group is substitutedwith one or more groups independently selected from hydrogen, halogen,nitro, cyano, methanesulfonyl, trifluoromethyl, trifluoromethoxy,difluoromethoxy, phenyl, a C₁-C₆ linear or branched alkyl group, and aC₁-C₆ linear or branched alkoxy group, and Z is a halogen.
 8. The methodof claim 1, wherein a piperidine compound of structural formula (I) andpharmaceutically acceptable salts thereof is prepared by the methodcomprising, preparing a piperidine compound of structural formula (VI)and pharmaceutically acceptable salts thereof, by reacting the compoundrepresented by structural formula (XXXIII) with a Weinreb amiderepresented by the following general structural formula (XIV) and vinylmagnesium bromide and NaBH_(4;)

reacting the piperidine compound represented by structural formula (VI)with 1,1′-carbonyldiimidazole (CDI); and reacting with an amine compoundrepresented by structural formula (VIII):

wherein, m is an integer of 1 or 2; n is an integer from 0 to 2; A isselected from a phenyl group and a benzimidazole group, wherein thephenyl group is substituted with one or more groups independentlyselected from hydrogen, a C₁-C₆ linear or branched alkyl group, a C₁-C₆linear or branched alkoxy group, an amino group, and a halogen, and thebenzimidazole group is substituted with one or more groups independentlyselected from hydrogen, a C₁-C₆ linear or branched alkyl group, a C₁-C₆linear or branched alkoxy group, a C₃-C₇ cyclic alkyl group, an aminogroup, a halogen, and an oxo group; B is selected from a phenyl group, aphenoxy group, a thienyl group, and a naphthyl group, wherein the phenylgroup, phenoxy group, thienyl group, or naphthyl group is substitutedwith one or more groups independently selected from hydrogen, halogen,nitro, cyano, methanesulfonyl, trifluoromethyl, trifluoromethoxy,difluoromethoxy, phenyl, a C₁-C₆ linear or branched alkyl group, and aC₁-C₆ linear or branched alkoxy group, and Z is a halogen.